Penicillin Classification, Mechanism of Action, Structure Activity Relationship, Structure of Penicillins, penicillin-binding proteins (PBPs) functional propertiesCross-linking of the peptidoglycan by transpeptidases, Cross-linking of the peptidoglycan by transpeptidases, Shape of penicillin G Penicillin SAR AcylSide Chain Modifications Instability of β-lactams to nucleophiles
Penicillinase-Resistant Penicillins Protein Binding of Penicillins
002. Cephalosporins for students 2023 Prof. P. Ravisankar.pdfDr. Ravi Sankar
Cephalosporins, Why Cephalosporins? Advantages of cephalosporins over penicillin, Mechanism of action of cephalosporins, Classification of cephalosporins, Structures of some important cephalosporins and cephamycins, Oximinocephalosporins, SAR of cephalosporins,Hydrolytic reactions, degradation and stability of cephalosporins, Uses of cephalosporins, Comparison between 6-APA and 7-ACA and penam and cepham.
synthetic antimicrobials having a quinolone structure that are active primarily against gram-negative bacteria, though newer fluorinated compounds also inhibit gram-positive ones.
Pharmacology of Penicllins (Beta lactam antibiotics), description of their mechanism of action, mechanism of resistance, classification, indications and adverse effects
The most common mode of action for antibiotics is the inhibition of cell wall synthesis. Antibiotics that inhibit cell wall synthesis work because of the fact that most eubacteria have peptidoglycan-based cell walls but mammals do not. Growth is prevented by inhibiting peptidoglycan synthesis. Thus these antibiotics only work for actively growing bacteria. The cell wall of new bacteria that grew in the presence of cell-wall-synthesis inhibitors is deprived of peptidoglycan. These bacteria will be subjected to osmotic lysis.In addition, gram-negative bacteria generally are less susceptible to inhibitors of cell wall synthesis than are gram-positive bacteria. In the former cell wall synthesis inhibitors fail to reach the cell wall because they are blocked by the gram-negative outer membrane.Penicillin is the classic example of an inhibitor of cell wall synthesis. Other examples include: ampicillin, bacitracin, carbapenems, cephalosporin, methicillin, oxacillin and vancomycin
Tetracyclines slide contains full information about uses, adverse effect, marketed preparation, precaution, route of drug administration, antimicrobial spectrum, mechanism of action, pharmacokineticks and pharmacodynamics of tetracyclines. This slide is very helpful for pharmacy and pharmacology student for the study about tetracyclines.
Broad spectrum antibiotics chloramphenicol, anaerobic,soil bacteria. Description includes Physicochemical Properties,Mechanism of action-50S ribosome ,Inhibits Bacterial protein synthesis,Resistance,Interactions,Indications of chloramphenicol-Pyogenic meningitis.
Anaerobic infections.
Intraocular infections.
Enteric fever
Drug of choice in some conditions.
Urinary tract infections
Topically In conjunctivitis & external ear Infections. Snehal chakorkar
This ppt deals with the sulfonamide group of drugs with classification, mechanism, spectrum, resistance, uses and adverse effects discussed in detail. It also discusses in detail about Cotrimoxazole
Introduction to Antibiotics,Classification,General Mechanism of action,Penicillin,Classification of Penicillin,Moa,Structure Activity Relationship,Uses
002. Cephalosporins for students 2023 Prof. P. Ravisankar.pdfDr. Ravi Sankar
Cephalosporins, Why Cephalosporins? Advantages of cephalosporins over penicillin, Mechanism of action of cephalosporins, Classification of cephalosporins, Structures of some important cephalosporins and cephamycins, Oximinocephalosporins, SAR of cephalosporins,Hydrolytic reactions, degradation and stability of cephalosporins, Uses of cephalosporins, Comparison between 6-APA and 7-ACA and penam and cepham.
synthetic antimicrobials having a quinolone structure that are active primarily against gram-negative bacteria, though newer fluorinated compounds also inhibit gram-positive ones.
Pharmacology of Penicllins (Beta lactam antibiotics), description of their mechanism of action, mechanism of resistance, classification, indications and adverse effects
The most common mode of action for antibiotics is the inhibition of cell wall synthesis. Antibiotics that inhibit cell wall synthesis work because of the fact that most eubacteria have peptidoglycan-based cell walls but mammals do not. Growth is prevented by inhibiting peptidoglycan synthesis. Thus these antibiotics only work for actively growing bacteria. The cell wall of new bacteria that grew in the presence of cell-wall-synthesis inhibitors is deprived of peptidoglycan. These bacteria will be subjected to osmotic lysis.In addition, gram-negative bacteria generally are less susceptible to inhibitors of cell wall synthesis than are gram-positive bacteria. In the former cell wall synthesis inhibitors fail to reach the cell wall because they are blocked by the gram-negative outer membrane.Penicillin is the classic example of an inhibitor of cell wall synthesis. Other examples include: ampicillin, bacitracin, carbapenems, cephalosporin, methicillin, oxacillin and vancomycin
Tetracyclines slide contains full information about uses, adverse effect, marketed preparation, precaution, route of drug administration, antimicrobial spectrum, mechanism of action, pharmacokineticks and pharmacodynamics of tetracyclines. This slide is very helpful for pharmacy and pharmacology student for the study about tetracyclines.
Broad spectrum antibiotics chloramphenicol, anaerobic,soil bacteria. Description includes Physicochemical Properties,Mechanism of action-50S ribosome ,Inhibits Bacterial protein synthesis,Resistance,Interactions,Indications of chloramphenicol-Pyogenic meningitis.
Anaerobic infections.
Intraocular infections.
Enteric fever
Drug of choice in some conditions.
Urinary tract infections
Topically In conjunctivitis & external ear Infections. Snehal chakorkar
This ppt deals with the sulfonamide group of drugs with classification, mechanism, spectrum, resistance, uses and adverse effects discussed in detail. It also discusses in detail about Cotrimoxazole
Introduction to Antibiotics,Classification,General Mechanism of action,Penicillin,Classification of Penicillin,Moa,Structure Activity Relationship,Uses
Mangal Yallappa Kamble
M pharm First Year
Pharmaceutical Chemistry Department
Dr. D.Y. Patil College of Pharmacy Akurdi, Pune.
Savitribai Phule University.
Sulphonamides, MOA, SAR, History of development, Nomenclature of the Sulfonamides, Classification, Spectrum of Action of the Sulfonamides,Structure Activity Relationship, Reducing Toxicity, Cotrimoxazole
nalidixic acid, the quinolones, the naphthyridines & the cinnolines, Classification, ISOSTERIC REPLACEMENT
DNA gyrase (Topo II) SAR- substitution variation, Ciprofloxacin
Epistemic Interaction - tuning interfaces to provide information for AI supportAlan Dix
Paper presented at SYNERGY workshop at AVI 2024, Genoa, Italy. 3rd June 2024
https://alandix.com/academic/papers/synergy2024-epistemic/
As machine learning integrates deeper into human-computer interactions, the concept of epistemic interaction emerges, aiming to refine these interactions to enhance system adaptability. This approach encourages minor, intentional adjustments in user behaviour to enrich the data available for system learning. This paper introduces epistemic interaction within the context of human-system communication, illustrating how deliberate interaction design can improve system understanding and adaptation. Through concrete examples, we demonstrate the potential of epistemic interaction to significantly advance human-computer interaction by leveraging intuitive human communication strategies to inform system design and functionality, offering a novel pathway for enriching user-system engagements.
Encryption in Microsoft 365 - ExpertsLive Netherlands 2024Albert Hoitingh
In this session I delve into the encryption technology used in Microsoft 365 and Microsoft Purview. Including the concepts of Customer Key and Double Key Encryption.
Builder.ai Founder Sachin Dev Duggal's Strategic Approach to Create an Innova...Ramesh Iyer
In today's fast-changing business world, Companies that adapt and embrace new ideas often need help to keep up with the competition. However, fostering a culture of innovation takes much work. It takes vision, leadership and willingness to take risks in the right proportion. Sachin Dev Duggal, co-founder of Builder.ai, has perfected the art of this balance, creating a company culture where creativity and growth are nurtured at each stage.
Essentials of Automations: Optimizing FME Workflows with ParametersSafe Software
Are you looking to streamline your workflows and boost your projects’ efficiency? Do you find yourself searching for ways to add flexibility and control over your FME workflows? If so, you’re in the right place.
Join us for an insightful dive into the world of FME parameters, a critical element in optimizing workflow efficiency. This webinar marks the beginning of our three-part “Essentials of Automation” series. This first webinar is designed to equip you with the knowledge and skills to utilize parameters effectively: enhancing the flexibility, maintainability, and user control of your FME projects.
Here’s what you’ll gain:
- Essentials of FME Parameters: Understand the pivotal role of parameters, including Reader/Writer, Transformer, User, and FME Flow categories. Discover how they are the key to unlocking automation and optimization within your workflows.
- Practical Applications in FME Form: Delve into key user parameter types including choice, connections, and file URLs. Allow users to control how a workflow runs, making your workflows more reusable. Learn to import values and deliver the best user experience for your workflows while enhancing accuracy.
- Optimization Strategies in FME Flow: Explore the creation and strategic deployment of parameters in FME Flow, including the use of deployment and geometry parameters, to maximize workflow efficiency.
- Pro Tips for Success: Gain insights on parameterizing connections and leveraging new features like Conditional Visibility for clarity and simplicity.
We’ll wrap up with a glimpse into future webinars, followed by a Q&A session to address your specific questions surrounding this topic.
Don’t miss this opportunity to elevate your FME expertise and drive your projects to new heights of efficiency.
Neuro-symbolic is not enough, we need neuro-*semantic*Frank van Harmelen
Neuro-symbolic (NeSy) AI is on the rise. However, simply machine learning on just any symbolic structure is not sufficient to really harvest the gains of NeSy. These will only be gained when the symbolic structures have an actual semantics. I give an operational definition of semantics as “predictable inference”.
All of this illustrated with link prediction over knowledge graphs, but the argument is general.
UiPath Test Automation using UiPath Test Suite series, part 4DianaGray10
Welcome to UiPath Test Automation using UiPath Test Suite series part 4. In this session, we will cover Test Manager overview along with SAP heatmap.
The UiPath Test Manager overview with SAP heatmap webinar offers a concise yet comprehensive exploration of the role of a Test Manager within SAP environments, coupled with the utilization of heatmaps for effective testing strategies.
Participants will gain insights into the responsibilities, challenges, and best practices associated with test management in SAP projects. Additionally, the webinar delves into the significance of heatmaps as a visual aid for identifying testing priorities, areas of risk, and resource allocation within SAP landscapes. Through this session, attendees can expect to enhance their understanding of test management principles while learning practical approaches to optimize testing processes in SAP environments using heatmap visualization techniques
What will you get from this session?
1. Insights into SAP testing best practices
2. Heatmap utilization for testing
3. Optimization of testing processes
4. Demo
Topics covered:
Execution from the test manager
Orchestrator execution result
Defect reporting
SAP heatmap example with demo
Speaker:
Deepak Rai, Automation Practice Lead, Boundaryless Group and UiPath MVP
GraphRAG is All You need? LLM & Knowledge GraphGuy Korland
Guy Korland, CEO and Co-founder of FalkorDB, will review two articles on the integration of language models with knowledge graphs.
1. Unifying Large Language Models and Knowledge Graphs: A Roadmap.
https://arxiv.org/abs/2306.08302
2. Microsoft Research's GraphRAG paper and a review paper on various uses of knowledge graphs:
https://www.microsoft.com/en-us/research/blog/graphrag-unlocking-llm-discovery-on-narrative-private-data/
GDG Cloud Southlake #33: Boule & Rebala: Effective AppSec in SDLC using Deplo...James Anderson
Effective Application Security in Software Delivery lifecycle using Deployment Firewall and DBOM
The modern software delivery process (or the CI/CD process) includes many tools, distributed teams, open-source code, and cloud platforms. Constant focus on speed to release software to market, along with the traditional slow and manual security checks has caused gaps in continuous security as an important piece in the software supply chain. Today organizations feel more susceptible to external and internal cyber threats due to the vast attack surface in their applications supply chain and the lack of end-to-end governance and risk management.
The software team must secure its software delivery process to avoid vulnerability and security breaches. This needs to be achieved with existing tool chains and without extensive rework of the delivery processes. This talk will present strategies and techniques for providing visibility into the true risk of the existing vulnerabilities, preventing the introduction of security issues in the software, resolving vulnerabilities in production environments quickly, and capturing the deployment bill of materials (DBOM).
Speakers:
Bob Boule
Robert Boule is a technology enthusiast with PASSION for technology and making things work along with a knack for helping others understand how things work. He comes with around 20 years of solution engineering experience in application security, software continuous delivery, and SaaS platforms. He is known for his dynamic presentations in CI/CD and application security integrated in software delivery lifecycle.
Gopinath Rebala
Gopinath Rebala is the CTO of OpsMx, where he has overall responsibility for the machine learning and data processing architectures for Secure Software Delivery. Gopi also has a strong connection with our customers, leading design and architecture for strategic implementations. Gopi is a frequent speaker and well-known leader in continuous delivery and integrating security into software delivery.
Accelerate your Kubernetes clusters with Varnish CachingThijs Feryn
A presentation about the usage and availability of Varnish on Kubernetes. This talk explores the capabilities of Varnish caching and shows how to use the Varnish Helm chart to deploy it to Kubernetes.
This presentation was delivered at K8SUG Singapore. See https://feryn.eu/presentations/accelerate-your-kubernetes-clusters-with-varnish-caching-k8sug-singapore-28-2024 for more details.
Elevating Tactical DDD Patterns Through Object CalisthenicsDorra BARTAGUIZ
After immersing yourself in the blue book and its red counterpart, attending DDD-focused conferences, and applying tactical patterns, you're left with a crucial question: How do I ensure my design is effective? Tactical patterns within Domain-Driven Design (DDD) serve as guiding principles for creating clear and manageable domain models. However, achieving success with these patterns requires additional guidance. Interestingly, we've observed that a set of constraints initially designed for training purposes remarkably aligns with effective pattern implementation, offering a more ‘mechanical’ approach. Let's explore together how Object Calisthenics can elevate the design of your tactical DDD patterns, offering concrete help for those venturing into DDD for the first time!
State of ICS and IoT Cyber Threat Landscape Report 2024 previewPrayukth K V
The IoT and OT threat landscape report has been prepared by the Threat Research Team at Sectrio using data from Sectrio, cyber threat intelligence farming facilities spread across over 85 cities around the world. In addition, Sectrio also runs AI-based advanced threat and payload engagement facilities that serve as sinks to attract and engage sophisticated threat actors, and newer malware including new variants and latent threats that are at an earlier stage of development.
The latest edition of the OT/ICS and IoT security Threat Landscape Report 2024 also covers:
State of global ICS asset and network exposure
Sectoral targets and attacks as well as the cost of ransom
Global APT activity, AI usage, actor and tactic profiles, and implications
Rise in volumes of AI-powered cyberattacks
Major cyber events in 2024
Malware and malicious payload trends
Cyberattack types and targets
Vulnerability exploit attempts on CVEs
Attacks on counties – USA
Expansion of bot farms – how, where, and why
In-depth analysis of the cyber threat landscape across North America, South America, Europe, APAC, and the Middle East
Why are attacks on smart factories rising?
Cyber risk predictions
Axis of attacks – Europe
Systemic attacks in the Middle East
Download the full report from here:
https://sectrio.com/resources/ot-threat-landscape-reports/sectrio-releases-ot-ics-and-iot-security-threat-landscape-report-2024/
Software Delivery At the Speed of AI: Inflectra Invests In AI-Powered QualityInflectra
In this insightful webinar, Inflectra explores how artificial intelligence (AI) is transforming software development and testing. Discover how AI-powered tools are revolutionizing every stage of the software development lifecycle (SDLC), from design and prototyping to testing, deployment, and monitoring.
Learn about:
• The Future of Testing: How AI is shifting testing towards verification, analysis, and higher-level skills, while reducing repetitive tasks.
• Test Automation: How AI-powered test case generation, optimization, and self-healing tests are making testing more efficient and effective.
• Visual Testing: Explore the emerging capabilities of AI in visual testing and how it's set to revolutionize UI verification.
• Inflectra's AI Solutions: See demonstrations of Inflectra's cutting-edge AI tools like the ChatGPT plugin and Azure Open AI platform, designed to streamline your testing process.
Whether you're a developer, tester, or QA professional, this webinar will give you valuable insights into how AI is shaping the future of software delivery.
2. INTRODUCTION
• Antibiosis-process by which one organism destroys
another to preserve itself by producing a metabolite &
the metabolic substance is Antibiotic
• Definition : A substance produced by microorganisms,
which has capacity of inhibiting the growth or
destroying other microorganisms at low
concentrations without affecting host to a
considerable extent.
3. INTRODUCTION
A substance is classified as an antibiotic if
• It is a product of metabolism (although it may be duplicated or
even have been anticipated by chemical synthesis).
• It is a synthetic product produced as a structural analog of a
naturally occurring antibiotic.
• It antagonizes the growth or survival of one or more species of
microorganisms.
• It is effective in low concentrations.
4. HISTORY OF ANTIBIOTICS
• 500-600 BC molded curd of soyabean used to treat boils &
carbuncles in Chinese folk medicine.
• Moldy Cheese to treat wounds in Ukraine
• 1877- Pasteur & Jobuert – anthrax bacilli killed in presence of
certain bacteria
• 1889 – Vuilemin coined termed antibiosis (against life)
• 1929 – Alexander Fleming accidental discovery of antibacterial
effects of penicillium.
• 1938- florey & Chain brought Penicillin in Clinical practice
• Waksman proposed defination of anitbiotics
5. CURRENT STATUS OF ANTIBIOTICS
• Commercial and scientific interest
• Thousands isolated& identified antibiotic substances
• Numerous semisynthetic and synthetic derivatives
8. SELECTING A METABOLITE AS A
ANTIBIOTIC
In addition to the ability to combat infections or neoplastic disease, the
antibiotic must possess
• First, selective toxicity to be effective against pathogenic microorganisms/
neoplastic tissue, without causing significant toxic effects.
• Second, chemically stable when isolated, processed, and stored for a reasonable
length of time without deterioration of potency & then convereted to suitable
dosage forms to provide active drug in vivo.
• Third, biotransformation and elimination should be slow enough to allow a
convenient dosing schedule, yet rapid and complete enough to facilitate removal
of the drug and its metabolites from the body soon after administration has
been discontinued.
• Some groups of antibiotics, because of certain unique properties, have been
designated for specialized uses, such as the treatment of tuberculosis(TB) or
fungal infections or anticancer.
• Also used in animal and plant disease too..
9. MECHANISMS OF ANTIBIOTIC
ACTION
Site of
action
Antibiotic Process interrupted Type of
Activity
Cell wall Bacitracin Mucopeptide synthesis Bactericidal
Cephalosporin Cell wall cross-linking Bactericidal
Cycloserine Synthesis of cell wall
peptides
Bactericidal
Penicillins Cell wall cross-linking Bactericidal
Vancomycin Mucopeptide synthesis Bactericidal
Cell
membrane
Amphotericin
B
Membrane function Fungicidal
Nystatin Membrane function Fungicidal
10. MECHANISMS OF ANTIBIOTIC
ACTION
Site of
action
Antibiotic Process interrupted Type of
Activity
Ribosomes
50S subunit
Chloramphenic
ol
Protein synthesis Bacteriostatic
Erythromycin Protein synthesis Bacteriostatic
Lincomycins Protein synthesis Bacteriostatic
30S subunit Aminoglycosid
es
Protein synthesis and fidelity Bactericidal
Tetracyclines Protein synthesis Bacteriostatic
Nucleic
acids
Actinomycin DNA and mRNA synthesis Pancidal
Griseofulvin Cell division, microtubule
assembly
Fungistatic
11. ΒETA-LACTAMS
• Possess β-lactam (4-membered cyclic amide) ring
structure are the dominant class of agents
• Used for the chemotherapy of bacterial infections.
• The 1st antibiotic to be used in therapy, penicillin
(penicillin G),
• Phenoxymethyl penicillin (penicillin V) biosynthetic are
first choice for the treatment of infections caused by most
species of Gram-positive bacteria.
• Penicillins & cephalosporins are resistant to penicillinase-
producing staphylococci and Gram-negative bacilli.
12. PENICILLIN CLASS DRUGS
• Ampicillin
• Amoxacillin
• Bacampicillin
• Benzylpenicillin
• Carbenicillin and indanyl
carbenicillin
• Clavulanic acid
• Methicillin
• Mezlocillin and piperacillin
• Nafcillin
• Oxacillin, cloxacillin, and
dicloxacillin
• Phenoxymethyl penicillin
• Piperacillin and tazobactam
• Sulbactam
• Ticarcillin
16. BETA-LACTAM
• A beta-lactam (β-lactam) ring is a four-membered
lactam.
• A lactam is a cyclic amide, and beta-lactams are
named so because the nitrogen atom is attached to
the β-carbon atom relative to the carbonyl.
• The simplest β-lactam possible is 2-azetidinone.
19. NUMBERING
SYSTEMS
Two numbering systems for the
fused bicyclic heterocyclic
system exist.
The Chemical Abstracts system
initiates the numbering with the
sulfur atom and assigns the ring
nitrogen the 4-position.
4-thia-l-
azabicyclo[3.2.0]heptanes,
The numbering system adopted
by the USP is the reverse of the
Chemical Abstracts procedure,
assigning number 1 to the
nitrogen atom & number 4 to the
26. MECHANISM OF ACTION
• Two properties contribute to the unequaled importance of β-lactam
antibiotics in chemotherapy:
1. Potent and rapid bactericidal action against bacteria in the growth phase and
2. Very low frequency of toxic and other adverse reactions in the host.
• The uniquely lethal antibacterial action of these agents has been
attributed to a selective inhibition of bacterial cell wall synthesis.
• Specifically, the basic mechanism involved is inhibition of the
biosynthesis of the dipeptidoglycan that provides strength and rigidity
to the cell wall.
27. MECHANISM OF ACTION
• Penicillins and cephalosporins acylate a specific bacterial D-
transpeptidase, thereby rendering it inactive for its role in forming
peptide cross-links of two linear peptidoglycan strands by
transpeptidation and loss of D-alanine.
• Bacterial D-alanine carboxypeptidases are also inhibited by beta-
lactam antibiotics.
28. MECHANISM OF ACTION
• Penicillins and cephalosporins acylate a specific bacterial D-transpeptidase,
thereby rendering it inactive for its role in forming peptide cross-links of two
linear peptidoglycan strands by transpeptidation and loss of D-alanine.
• Bacterial D-alanine carboxypeptidases are also inhibited by Beta-lactam
antibiotics.
• Binding studies with tritiated benzylpenicillin have shown that the
mechanisms of action of various beta–lactam antibiotics are much more
complex than previously assumed.
• Studies in E. coli have revealed as many as seven different functional proteins,
each with an important role incell wall biosynthesis.
29. PENICILLIN-BINDING PROTEINS (PBPS)
FUNCTIONAL PROPERTIES
• PBPs 1a and 1b are transpeptidases involved in peptidoglycan synthesis
associated with cell elongation.
• Inhibition results in spheroplast formation and rapid cell lysis, caused by
autolysins (bacterial enzymes that create nicks in the cell wall for
attachment of new peptidoglycan units or for separation of daughter cells
during cell division10).
• PBP 2 is a transpeptidase involved in maintaining the rod shape of bacilli.
• Inhibition results in ovoid or round forms that undergo delayed lysis.
• PBP 3 is a transpeptidase required for septum formation during cell
division.
• Inhibition results in the formation of filamentous forms containing rod-
shaped units that cannot separate. It is not yet clear whether inhibition of
PBP 3 is lethal to the bacterium.
30. PENICILLIN-BINDING PROTEINS (PBPS)
FUNCTIONAL PROPERTIES
• PBPs 4 through 6 are carboxypeptidases responsible for the hydrolysis of
D-alanine–D-alanine terminal peptide bonds of the cross-linking peptides.
• Inhibition of these enzymes is apparently not lethal to the bacterium,13
even though cleavage of the terminal D-alanine bond is required before
peptide cross-linkage.
• The various Beta-lactam antibiotics differ in their affinities for PBPs.
• Penicillin G binds preferentially to PBP 3, whereas
• the first-generation cephalosporins bind with higher affinity to PBP 1a.
• In contrast to other penicillins and to cephalosporins, which can bind to
PBPs 1, 2, and 3, amdinocillin binds only to PBP 2
37. PENICILLIN SAR
No Substitution
allowed
Sulphur is
required but not
mandatory
Thiazolidine ring,
essential for
activity
Carboxylic Acid:
Involved in ionic
interactions with N of lysine
at binding site
Activity ↓ if reduced by -
COOR or -CHOH
Trans -
stereochemistry is
required with COOH
Acylamino sidechain:
EWG make amide less
Nucleophilic,
Bulky gr provides steric
hindrance to β-lactamase
Polar grs make it more
hydrophobic
Carbonyl Group:
Lone pair e- of N do not
resonate to carbonyl
group hence is venerable
to nucleophilic attack
Bicyclic system :
Puts a strain on the β-lactam ring
Strain directly proportional to instability
of the structure
β-lactam
strained ring
Dimethyl group:
Essential, removal
↓activity
39. SAR
• Position 1 – When the sulfur atom of the Thiazolidine ring is oxidized to a
sulfone or sulfoxide, it improves acid stability, but decreases the activity of the
agent. It is replaceable as in case with Carbapenems
• Position 2 – No substitutions allow at this position, any change will lower
activity. The methyl groups are necessary
• Position 3 – The carboxylic acid of the Thiazolidine is required for activity. It
ionizes & the has ionic interactions with a lysine moiety at receptor site increase
the affinity towards the macromolecule. If it is changed to an alcohol or ester,
activity is decreased.
• Position 4 – The nitrogen is a must.
• Position 5 – No substitutions allowed.
40. SAR
• Position 7 – The carbonyl on the Beta-lactam ring is a must.
• Position 6 – Substitutions are allowed on the side chain of the
amide.
• An electron withdrawing group added at this position will
give the compound better acid stability because this
substitution will make the amide oxygen less nucleophillic.
• A bulky group added close to the ring will make the
compound more resistant to Beta-lactamases.
• Steric hindrance provides protect to the Beta-lactam ring.
41. Β-LACTAM RING OPENING BY
ACYLAMINO SIDE-CHAIN
• the acylamino side-chain can help aid the ring-opening of the β-
lactam ring.
• It can act as an internal nucleophile and attack the β-lactam carbonyl
forming a very strained intermediate that then opens to break the β-
lactam ring.
• This makes the penicillin inactive and is sometimes described as a
‘self-destruct’ mechanism.
42. MODIFICATION OF ACYLAMINO SIDE-
CHAIN
• Placing an electron-withdrawing substituent(EWS) within the side-
chain reduces nucleophilicity of acyl carbonyl
• The EWS group accepts electrons & makes the amide carbonyl
group a weaker nucleophile, which is less likely to react with the β-
lactam carbonyl.
• For example, penicillin G is more prone to ‘self-destruct’ than
penicillin V, or phenoxymethylpenicillin.
43. PENICILLIN STEREOCHEMISTRY
• C5 & C6 –H should have cis orientation.
• C6 –NH2 & C2 –COOH should have trans orientation.
• Change in orientation increases instability & hence reduces activity.
48. Β-LACTAMASE RESISTANT/SENSITIVE
STRUCTURAL FEATURES
• When the aromatic ring is attached directly to the side chain carbonyl and
both ortho-positions are substituted by methoxy groups,b-lactamase stability
results
• Movement of one of the methoxy groups to the para position or replacing one
of them with a hydrogen results in an analog sensitive to beta-lactamases.
• Putting in a methylene between the aromatic ring and 6-APA likewise
produces a b-lactamase–sensitive agent
49. Β-LACTAMASE RESISTANT/SENSITIVE
STRUCTURAL FEATURES
• Stability of the penicillins toward β-lactamase is influenced by the
bulk in the acyl group attached to the primary amine.
• β-Lactamases are much less tolerant to the presence of steric
hindrance near the side-chain amide bond than are the penicillin
binding proteins(PBPs).
• When the aromatic ring is attached directly to the side-chain
carbonyl and both ortho-positions are substituted by methoxy
groups, β-lactamase stability results
50. BETA-LACTAMASE
RESISTANT/SENSITIVE STRUCTURAL
FEATURES
• Movement of one of the methoxy groups to the para-position, or
replacing one of them by a hydrogen, resulted in an analogue sensitive
to β-lactamases.
• Putting in a methylene between the aromatic ring and 6-APA likewise
produced a β-lactamase–sensitive agent.
• These findings provide strong support for the hypothesis that its
resistance to enzyme degradation is based on differential steric
hindrance.
• Prime examples of this effect are seen in the drugs methicillin, nafcillin,
54. METHICILLIN
• Methicillin is the first of the penicillinase-resistant agents to reach the
clinic.
• It is unstable to gastric acid, having a half- life of 5 minutes at pH 2, so it has
to be administer via injection.
• Increased bulk resulting from the addition of the dimethoxybenzoyl group
to 6-APA leads to methicillin being a b-lactamase–resistant drug.
• Methicillin has significantly narrower antimicrobial spectrum and less
potency.
55. METHICILLIN
• Substitutions at the ortho positions of a phenylring increase the steric
hindrance of the acyl group and confer more beta-lactamase resistance than
shown by the unsubstituted compounds or those substituted at positions more
distant from the alpha-carbon.
• Bulkier substituents are required to confer effective beta-lactamase resistance
among five-membered–ring heterocyclic derivatives
• Clinical use primarily for parenteral use in infections due to b-lactamase
producing S. aureus and a few other infections.
• An increasing number of infections are caused by MRSA.
• In these organisms, an altered PBP is formed that has a very low affi nity for
beta-lactams, excluding ceftaroline.
• Furthermore, methicillin is an efficient inducer of penicillinases.
• Consequently this drug fell out of favor, and methicillin has now been replaced.
56. NAFCILLIN
• Nafcillin has a 2-ethoxynaphthylside chain.
• This bulky group serves to inhibit destruction by b-
lactamases analogous to methicillin.
• Although slightly more acid stable than methicillin, it is
clinically virtually identical to it.
57. OXACILLIN & DICLOXACILLIN
• Using a substituted isoxazolyl ring as a bioisosteric replacement for
the benzene ring of penicillin G produces the isoxazolyl penicillins.
• Chemically, they differ from one another by chlorine substituents on
the benzene ring.
• Like methicillin, these are generally less potent than
benzylpenicillin against gram-positive microorganisms (generally
staphylococci and streptococci) that do not produce a b-lactamase
but retain their potency against those that do.
• They are more acid stable; thus they may be taken orally, and they
are more potent as well.
58. OXACILLIN & DICLOXACILLIN
• Because they are highly serum protein bound, they are not good
choices for treatment of septicemia.
• Microorganisms resistant against methicillin are also resistant to the
isoxazolyl group of penicillins.
• Like nafcillin, the isoxazolyl group of penicillins is primarily used
against penicillinase-producing Staphylococcus aureus
60. AMPICILLIN
• One of the hydrogen atoms of the side chain methylene has been replaced
with a primary amino group to produce an R-phenylglycine moiety .
• Significant acid stability - oral use.
• Gram-negative pathogens are sensitive to ampicillin.
• Greater penetration of ampicillin into gram negative bacteria.
• The acid stability is due to electron-withdrawing character of the
protonated primary amine group reducing participation in hydrolysis of the
b-lactam bond as well as to the comparative difficulty of bringing another
positively charged species (H3O+) into the vicinity of the protonated amino
group.
• The oral activity is also enhanced, in part, to active uptake by the dipeptide
transporters.
• It unfortunately lacks stability toward b-lactamases, and resistance is
increasingly common.
61. BACAMPICILLIN
• Prodrug
• It is a weak base and is very well absorbed in the duodenum.
• Enzymatic ester hydrolysis in the gut wall liberates carbon
dioxide and ethanol followed by spontaneous loss of
acetaldehyde and production of ampicillin.
• The acetaldehyde is metabolized oxidatively by alcohol
dehydrogenase to produce acetic acid, which joins the normal
metabolic pool.
• Amoxicillin, which has better oral availability than ampicillin has
made the reduced use of bacampicillin.
62. AMOXICILLIN
• Close analog of ampicillin
• para-phenolic hydroxyl group in the side-chain phenyl moiety.
• The isoelectric point of the drug to a more acidic value and has enhanced
blood levels as compared with ampicillin.
• Better oral absorption leads to less disturbance of the normal GI flora and,
therefore, less drug-induced diarrhea.
• The antimicrobial spectrum similar to ampicillin.
• Coadministered with clavulanic acid combination (Augmentin) in which the
clavulanic acid serves to protect amoxicillin to a considerable extent against
b-lactamases.
• This expands the spectrum of activity to include organisms and strains that
produce b-lactamases.
63. CARBENICILLIN
• Semisynthetic Penicillin (1970),
• It has an ionizable carboxyl group substituted on the alpha-
carbon atom of the benzyl side chain.
• Broad range of antimicrobial activity b’coz of the unique
carboxyl group.
• The carboxyl group improves penetration of the molecule
through cell wall barriers of Gram-negative bacilli, compared
with other penicillins.
• Carbenicillin is not stable in acids and is inactivated by
penicillinase.
• It is a malonic acid derivative and decarboxylates readily to
penicillin G, which is acid labile.
64. CARBENICILLIN
• Effective in the treatment of systemic & UTI caused by P.
aeruginosa, indole-producing Proteus spp., and Providencia
spp., all of which are resistant to ampicillin.
• The low toxicity permits the use of large dosages in serious
infections.
• A combination of carbenicillin and gentamicin is for serious
pseudomonal and mixed coliform infections. The two
antibiotics are chemically incompatible, however, and
should never be combined in an intravenous solution.
65. TICARCILLIN
• Ticarcillin disodium, 2-carboxy-3-thienylpenicillin (Ticar), is an
isostere of carbenicillin in which the phenyl group is replaced by a
thienyl group.
• This semisynthetic penicillin derivative, unstable in acid,
administered parenterally.
• It is similar to carbenicillin in antibacterial spectrum &
pharmacokinetic properties.
• Two advantages for ticarcillin are clamied:
(a) slightly better pharmacokinetic properties, including higher serum
levels and a longer duration of action; and
(b) greater in vitro potency against several species of Gramnegative
bacilli, most notably P. aeruginosa and Bacteroides fragilis.
• These advantages can be crucial in the treatment of serious
infections requiring high-dose therapy.
66. MEZLOCILLIN
• Acylureidopenicillin spectrum similar to
that of carbenicillin and ticarcillin;
however, there are some major
differences.
• It is much more active against most
Klebsiella spp., P. aeruginosa,
anaerobic bacteria (e.g., Streptococcus
faecalis and B. fragilis), and H.
influenzae.
• It is recommended for the treatment of
serious infections caused by these
organisms.
67. PIPERACILLIN
• Most useful of the extended-spectrum acylureidopenicillins.
• It is more active than mezlocillin against susceptible strains of Gram-
negative aerobic bacilli, such as Serratia marcescens, Proteus,
Enterobacter, Citrobacter spp., and P. aeruginosa.
• Mezlocillin, however, appears to be more active against Providencia spp.
and K. pneumoniae.
• Piperacillin is also active against anaerobic bacteria, especially B. fragilis
and S. faecalis (enterococcus).
• Beta-Lactamase–producing strains of these organisms are, however,
resistant to piperacillin, which is hydrolyzed by S. aureus beta-lactamase.
• The Beta- lactamase susceptibility of piperacillin is not absolute because
Beta- lactamase–producing, ampicillin-resistant strains of N. gonorrhoeae
and H. influenzae are susceptible to piperacillin.
The nomenclature of penicillins is somewhat complex and
very cumbersome. Two numbering systems for the fused bicyclic
heterocyclic system exist. The Chemical Abstracts
system initiates the numbering with the sulfur atom and assigns
the ring nitrogen the 4-position. Thus, penicillins are
named as 4-thia-l-azabicyclo[3.2.0]heptanes, according to
this system. The numbering system adopted by the USP is
the reverse of the Chemical Abstracts procedure, assigningnumber 1 to the nitrogen atom and number 4 to the sulfur
atom. Three simplified forms of penicillin nomenclature
have been adopted for general use. The first uses the name
“penam” for the unsubstituted bicyclic system, including the
amide carbonyl group, with one of the foregoing numbering
systems as just described. Thus, penicillins generally are
designated according to the Chemical Abstracts system as 5-
acylamino-2,2-dimethylpenam-3-carboxylic acids. The second,
seen more frequently in the medical literature, uses the
name “penicillanic acid” to describe the ring system with
substituents that are generally present (i.e., 2,2-dimethyl and
3-carboxyl). A third form, followed in this chapter, uses trivial
nomenclature to name the entire 6-carbonylaminopenicillanic
acid portion of the molecule penicillin and thendistinguishes compounds on the basis of the R group of the
acyl portion of the molecule. Thus, penicillin G is named
benzylpenicillin, penicillin V is phenoxymethylpenicillin,
methicillin is 2,6-dimethoxyphenylpenicillin, and so on. For
the most part, the latter two systems serve well for naming
and comparing closely similar penicillin structures, but they
are too restrictive to be applied to compounds with unusual
substituents or to ring-modified derivative
Penicillin acts by inhibiting the transpeptidase enzyme - it mimics a peptidoglycan chain and an ester is formed that joins the penicillin to the enzyme. As the penicillin group is so large, it prevents attack of a nucleophile at the ester carbonyl and so the ester does not react with the second peptidoglycan chain. With the enzyme unable to form cross-links the peptidoglycan wall begins to degrade. No new peptidoglycan chains can be added to the cell wall and eventually the cell bursts.
the basic structure of penicillin consists of a β-lactam ring and an acylamino side chain (RCONH–). Based on the mode of action, the β-lactam ring is clearly crucial for its biological activity – the carbon atom in the C=O of the lactam is particularly electrophilic (δ+) and the adjacent thiazolidine ring confers further strain on the β-lactam ring, making it even more reactive to nucleophilic attack. The carboxylic acid group is also important – this is normally deprotonated within the body and the negatively charged carboxylate ion (RCO2–) binds to a positively charged amino acid within the active site of the transpeptidase enzyme.
At the top of the β-lactam ring, a cis–arrangement of hydrogens (both on the same side of the ring) is required for the biological activity, as is an acylamino side chain at the ‘top left’.
This acts as an electron-withdrawing group (the nitrogen atom accepts electron density from the β-lactam carbonyl making it an even stronger electrophile).
Of the three C=O bonds in the penicillin, the β-lactam carbonyl is the most electrophilic. The C=O bond in the acylamino side-chain is not susceptible to nucleophilic attack, because, as is typical of amides, the nitrogen atom can feed its lone pair into the carbonyl group which makes it a weaker electrophile.
Similarly, the C=O bond in the carboxylic acid side-chain, or the carboxylate ion, is not susceptible to nucleophilic attack because the oxygen atom can feed its lone pair into the adjacent carbonyl group. (The wavy lines indicate only a partial structure is shown.)
At the top of the β-lactam ring, a cis–arrangement of hydrogens (both on the same side of the ring) is required for the biological activity, as is an acylamino side chain at the ‘top left’.
This acts as an electron-withdrawing group (the nitrogen atom accepts electron density from the β-lactam carbonyl making it an even stronger electrophile).
Of the three C=O bonds in the penicillin, the β-lactam carbonyl is the most electrophilic. The C=O bond in the acylamino side-chain is not susceptible to nucleophilic attack, because, as is typical of amides, the nitrogen atom can feed its lone pair into the carbonyl group which makes it a weaker electrophile.
Similarly, the C=O bond in the carboxylic acid side-chain, or the carboxylate ion, is not susceptible to nucleophilic attack because the oxygen atom can feed its lone pair into the adjacent carbonyl group. (The wavy lines indicate only a partial structure is shown.)
Penicillin V contains an electronegative oxygen in the PhO substituent, which draws the electron density away from the amide carbonyl group and so reduces its tendency to act as a nucleophile and react with the β-lactam ring. This has important consequences. While penicillin V is stable enough to survive the acidic aqueous conditions in the stomach and so can be taken as a tablet (which is typically preferred by patients), penicillin G does not and so needs to be administered by an injection.
At the top of the β-lactam ring, a cis–arrangement of hydrogens (both on the same side of the ring) is required for the biological activity, as is an acylamino side chain at the ‘top left’.
This acts as an electron-withdrawing group (the nitrogen atom accepts electron density from the β-lactam carbonyl making it an even stronger electrophile).
Of the three C=O bonds in the penicillin, the β-lactam carbonyl is the most electrophilic. The C=O bond in the acylamino side-chain is not susceptible to nucleophilic attack, because, as is typical of amides, the nitrogen atom can feed its lone pair into the carbonyl group which makes it a weaker electrophile.
Similarly, the C=O bond in the carboxylic acid side-chain, or the carboxylate ion, is not susceptible to nucleophilic attack because the oxygen atom can feed its lone pair into the adjacent carbonyl group. (The wavy lines indicate only a partial structure is shown.)
the basic structure of penicillin consists of a β-lactam ring and an acylamino side chain (RCONH–). Based on the mode of action, the β-lactam ring is clearly crucial for its biological activity – the carbon atom in the C=O of the lactam is particularly electrophilic (δ+) and the adjacent thiazolidine ring confers further strain on the β-lactam ring, making it even more reactive to nucleophilic attack
The substitution of a side-chain R group on the primary amine with an electron-withdrawing group decreases
the electron density on the side-chain carbonyl and protects these penicillins, in part , from acid degradation.
This property has clinical implications, because these compounds survive passage through the stomach
better and many can be given orally for systemic purposes. The survival of passage and degree of
absorption under fasting conditions is shown in Table
In addi tion, in vi tro degradat ion reactions of penici ll ins can be retarded by keeping the pH of solut ions
between 6.0 and 6.8 and by refrigerating them. Metal ions, such as mercury, zinc, and copper, catalyze the
degradat ion of penicil l ins, so they should be kept from contact wi th penici ll in solutions. The lids of
containers used today are routinely made of inert plast ics, in par t, to minimize such problems.