Pharmacy Antibiotic Table PHAR 747: Infectious Diseases

1. « β-Lactam Antibiotics »
Mechanism of Action Mechanism of Resistance
 β-Lactam antibiotics are bactericidal, and act by inhibiting the synthesis of the
peptidoglycan layer of bacterial cell walls
 The final transpeptidation step in the synthesis of the peptidoglycan is facilitated
by transpeptidases known as penicillin-binding proteins (PBPs)
 β-Lactam antibiotics are analogues of D-alanyl-D-alanine - the terminal amino acid
residues on the precursor NAM/NAG-peptide subunits of the peptidoglycan layer
 Similarity between β-lactam antibiotics and D-alanyl-D-alanine facilitates their
binding to the active site of penicillin-binding proteins (PBPs)
 β-lactam nucleus of the molecule irreversibly binds to (acylates) the SER of the
PBP active site, preventing the final crosslinking (transpeptidation) of the
peptidoglycan layer, disrupting bacterial cell wall biosynthesis
 Enzymatic hydrolysis of the β-lactam ring  if the bacterium produces the
enzyme β-lactamase or the enzyme penicillinase, the enzyme will break open the
β-lactam ring of the antibiotic, rendering the antibiotic ineffective
 Possession of altered penicillin-binding proteins  β-Lactams cannot bind as
effectively to these altered PBPs, and, as a result, the β-lactams are less effective
at disrupting cell wall synthesis
 Transpeptidase is located along the exterior of the cytoplasmic membrane 
Gram-(+) or in the periplasmic space  Gram-(-)
 Gram-(-)  L-Ala-γ-D-Glu-Dap-D-Ala-D-Ala or L-Ala-γ-D-Glu-L-Lys-D-Ala-D-Ala
 Gram-(+)  Short peptide (usually 5 Glycines) attached to Lysine; NH2 on the
terminal Glycine cross-links with the D-Ala of a second PG strand (Larger Gap)
 Penicillins  6-Aminopenicillanic Acid (6-APA), The Warhead; Ring Strain is Key (Azetidinone 4-Sided Ring)
Class Generic Name Brand Name PO IV Gram (+) Gram (–) β-LA Resistance Spectrum Note
Natural
Benzylpenicillin Penicillin G X Potent Hydrolyzed Narrow Poor amide resonance = fairly basic N
Phenoxymethylpenicillin Penicillin V X Potent Hydrolyzed Narrow EWG increase bioavailability; T1/2 = 5hrs
β-Lactamase
Resistant
Methicillin Staphcillin X Good Stable Narrow More acid Labile than Pen G
Nafcillin Unipen X Good Stable Narrow Most Active; mass-to-mass comparison
Oxacillin (X1 = X2 = H) Prostaphlin X Good Good Narrow Differ in the Halogen on Ring (EWG)
Order of increase H Stability (OCD)
↑ Acid Solubility = ↑EWG = Stable
Cloxacillin (X1 = Cl, X2 = H) Tegopen X Good Good Narrow
Dicloxacillin (X1 = X2 = Cl) Dynapen X Good Good Narrow
Aminopenicillin
Ampicillin (Bacampicillin) Polycillin X Good Low Hydrolyzed Moderate Prodrug-Hydro; R-isomer better for (G-)
Amoxicillin Amoxil X Good Low Hydrolyzed Moderate 2x better absorption; Less GI upset; #1
Carboxypenicillin
Carbenicillin Geopen X X Good Good Hydrolyzed Extended Racemize in Soln, Affect platelet=bleed
Ticarcillin Ticar X Good Good Hydrolyzed Extended Req High Dose (30-40g) QD, Thiophene
Acylureidopenicillin
Pipericillin Piperacil X Good Good Hydrolyzed Extended +20g QD, Bulk not close to block attack
Azlocillin Azlin X Good Good Hydrolyzed Extended More potent than Carbencillin, Acid
Labile; Mezlo forms sulfonamide
Mezlocillin Mezlin X Good Good Hydrolyzed Extended
 Cephalosporins  7-Amino Cephalosporanic Acid (7-ACA)  Must Have Free Carboxy @ C4 (1 or 2 Step Process)
Class Generic Name Brand Name PO IV Gram (+) Gram (–) β-LA Resistance Spectrum Note
1
st
Generation
Cephalothin Keflin X Good Modest Stable Moderate Thiophene; R2 = Acetoxymethyl -Activity
Cefazolin Ancef X Good Modest Stable Moderate Longest T1/2; 85% Serum Protein Bound
Cephalexin Keflex X Good Modest Stable Moderate Not metabolized (90% urine); UTI
2
nd
Generation
Cefuroxime (Axetil) Ceftin X X Good Modest Good Moderate Prodrug-Ester; Oxime Ether in Syn; CSF
Cefoxitin Mefoxin X Low Modest Good Moderate Anaerobes; Competitive Inhibitor
3
rd
Generation
Cefotaxime Claforan X Low Good Stable Broad Syn-Oxime Most Potent; Aminothiazole
Ceftriaxone Recephin X Low Good Stable Broad Tx: Gonorrhea; Long T1/2, QD; 95% SPB
4
th
Generation
Cefepime Maxipime X Good Good Stable Broad 100% Urine (UTI); Good access/conc CSF
Cefpirome Cefrom X Good Good Stable Broad Quaternary Amine (Neutral) Leaving Grp

2.  Monobactams  β-Lactam not Fused with Another Ring
Class Generic Name Brand Name PO IV Gram (+) Gram (–) β-LA Resistance Spectrum Note
Sulfonated
Sulfazecin Weak Weak Very Stable Weak Not used, C4 modification increase uses
Aztreonam Azactam X Good Very Stable Narrow Tx: P. aeriginosa in Cystic Fibrosis Pts
 Carbapenems  Suspsible to Metallo-β-Lactamases
Class Generic Name Brand Name PO IV Gram (+) Gram (–) β-LA Resistance Spectrum DHP-1 Note
Thienamycin
Derivative
Imepenem X Good Good Very Stable Very Broad Rapidly Hydrolyzed SE: Seizure; Not Abx, Reversible
Meropenem Merrem X Low Good Stable Very Broad Slowly Hydrolyzed Antipseudo; Pene. CSF, Heart, Lung
Ertapenem Invanz X Good Good Stable Very Broad Resistant QD dosing; Penetrate Porin Channel
Doripenem Doribax X Good Good Stable Very Broad Slowly Hydrolyzed Includes Anaerobes, Antipseudo
« β-Lactam Inhibitors »
Mechanism of Action Type of β-Lactamases
 Avoidance – alter the structure of the penicillin so it is no longer a substrate for
the β-lactamase  Successful but decrease antibacterial activity
 Neutralization – inhibit the β-lactamase while simultaneously administering a
penicillin that would otherwise be hydrolyzed
 The Serine β-Lactamases: Classes A, C & D
 Destroy the β-lactams antibiotics by a mechanism that is similar to how the
β-lactams inactivate the PBP targets BUT, the acyl-enzyme complex is
unstable  easily hydrolyzed by H2O
 Some achieved Catalytic Perfection  They catalyze as fast as they diffuse in
 Zinc-requiring β-lactamases (metallo-β-lactamases): Class B
 Catalyze the hydrolysis of S-D-lactoyl-glutathione to form glutathione and D-
lactic acid and a competence protein that is essential for natural
transformation and could be a transporter involved in DNA uptake. These
proteins bind two zinc ions per molecule as cofactor
 In Gram-(+) bacteria that produce β-lactamases the enzymes are secreted from
the cell or found along the exterior of the cytoplasmic membrane  Hydrolyzed
before reaching porous cell wall
 In Gram-(-) species the enzymes are found in the periplasmic space or bound to
the exterior of the cytoplasmic membrane  2
nd
line of defense if it makes it
through the outer membrane
 Class 1  Example Oxapenam
Inhibitor Antibiotic Used Brand Name PO IV Gram (+) Gram (–) Antibacterial Spectrum Note
Clavulanate
Amoxcillin Augmentin X X X Weak Broad Synergistic Effect coadmin with β-lactam;
Extends life of PCN (Sacrificial Pawn)
Ticarcillin Timentin X X X Weak Broad
Sulbactam Ampicillin Unasyn X X X Weak Broad Potentiates activity of ampicillin/carbenicllin
Tazobactam Pipericillin Zosyn X X X Weak Broad Synthetic; Triazole containing
 Class 2  Example Carbapenam
Inhibitor Antibiotic Used Brand Name PO IV Gram (+) Gram (–) Antibacterial Spectrum Note
Thienamycin Good Not used but a precursor to Carbapenems
Cilastatin Imepenem Primaxin X None None Inhibits Renal Dehydropeptidase-1 (DHP-1)

3. « Peptide Antibiotics »
General Mechanism of Action General Problems of Class
 Block cell wall biosynthesis by binding to peptidoglycan and its precursors
 Affects membrane permeability by forming pores (leaky) and alter functions
 Bactericidal and Inhibits protein biosynthesis
 Acid labile, Short duration, Enzymatically Hydrolyzed, Antigenic, Spendy, Toxicity
 Membrane is usually a problem cause its hard to differentiates from bacteria and
host cells  It attacks everything
 Peptides  Every Organism Produce some Type of Protective Peptide (Multi=Defensin; Uni=NRPS)
Mechanism of Action Mechanism of Resistance
 Blocks the diphosphatase that converts undecalprenyldiphosphate to
undecaprenylphosphate  Inhibits Translocation (Stalls assembly line)
 Inhibits recycling of the undecalprenyldiphophate lipid carrier (Building Blocks)
 Requires Zinc and Magnesium for activity
 Prevents Diphophatase from accessing the substrate
 Increased de novo synthesis of C-isoprenyl phosphates (IP) which is a carriers
during synthesis of the repeat subunits of peptidoglycan
 Substrate-Binding Inhibitor  Inhibits reaction by blocking substrate not enzyme
 Thiazoline Segment is Essential for Bioactivity
Class Generic Name Brand Name PO IV Gram (+) Gram (–) Side Effects Note
Cyclic Peptides Bacitracin Bacitracin Topical X Nephrotoxic Neosporin (Broad) = Bacitracin (+), Neomycin (+/-), Polymyxin (-)
Affect Cell
Membranes
Polymyxin/Colistin
Xignis Top/IV X Neuro/Nephro Tx: Sepsis (Endotoxin) and Septic Shock; Poor selective toxicity
MoA Complex Lipid A (LPS); affect permeability/disorganize MoR Target Modification by inducible electrostatic repulsion
Gramicidin
Topical X X Hemolysis Alternating D/L AA forms helix; Not charged, N=Formyl; C=Ethanol
MoA Form pores in G+ cytoplasmic membrane; Requires 2 helices to span membrane; Permits cations to escape, Depolarizing (K/Na)
Daptomycin
Cubicin X X Low/GI Prob Tx: SSSI and Infective Endocarditis/Bacteremia; MSSA, MRSA, VRE
MoA Ca
2+
Dependent Abx; Conformation  to pump, Depolarize MoR None are known, but can develop; No cross-resistance
Affect Protein
Synthesis
Quinu/Dalfo-pristin
(Streptogramin)
Synercid X X Pain Inject Site Tx: VRE/MRSA; -static alone, synergistic = -cidal; Inhibit CYP3A4
MoA 50S Bacterial Ribosomal; Prevent protein elongation MoR Drug Modifying Enzyme and Target Modification
 Glycopeptides  Family of Highly Modified Rigid Peptides with One or More Aminosugar
Mechanism of Action Mechanism of Resistance
 Inhibits both Transglycosylation AND Transpeptidation (Blocks PG elongation)
 Forms a strong non-covalent complex with D-Ala-D-Ala terminus of Lipid II and PG
 Prevents binding of the substrate to TPase/TGase causing steric bulk hindering
access to enzyme  Affects only the outer surface of the cells
 Inhibit the synthesis of cell walls in susceptible microbes by inhibiting PG
synthesis. They bind to the AA within the cell wall preventing the addition of new
units to the PG. They bind to acyl-D-alanyl-D-alanine in peptidoglycan.
 VanA: High-level resistance to both teicoplanin and vancomycin. Resistance is
induced by presence of the antibiotics. Resistance genes are transmitted between
bacteria on a transposon. VanA is the enzyme (a ligase) that forms the D-Ala-D-Lac
 VanB: Resistant to vancomycin but susceptible to teicoplanin. Resistance is only
induced by vancomycin. VanB is a ligase that forms the D-Ala-D-Lac
 VanC: Intrinsic resistance to vancomycin but not teicoplanin. Constitutive
expression of VanC gene that encodes VanC, a D-Ala-D-Ser ligase
Class Generic Name Brand Name PO IV Gram (+) Gram (–) Side Effects Note
Tricyclic Heptapeptide Vancomycin Vancocin X X X Nephro/Oto Toxic Oral Tx: C.Diff; Usually -cidal/static; Synergy with AG
1
st
Generation
Lipoglycopeptides
Teicoplanin Targocid X X Hypersensitivity 2
nd
MoA  Direct Inhibition of Transglycosylase
Telavancin Vibativ X X Hypersensitivity Antibacterial  Inhibit PG synthesis,  Permeability
2
nd
Generation
Lipglycopeptides
Dalbavancin Zeven X X Still in Trials Active vs VanB not VanA VRE; Greater potency; Qwk
Oritavancin X Still in Trials Active vs both VanA/VanB VRE; Strong –cidal; QD

4. « Aminoglycoside Antibiotics »
Mechanism of Action Mechanism of Resistance
 Transport  AGs alter the outer membrane of (G-) bacteria allowing penetration
through membrane and can pass through porins  AGs are actively transported
by an O2–dependent transport system (Low pH and anaerobic inhibit transport)
 Cellular Target  Bind to the16S rRNA component of the 30S ribosomal subunit
“irreversibly” inhibit protein biosynthesis = Bactericidal
 Interaction of AGs with the 16S rRNA of the 30S ribosomal subunit
 Numerous contacts are made mostly with nucleic acids NOT proteins
 Cause misreading of mRNA = Truncated proteins or proteins with the wrong amino
acid sequence that do not fold correctly = Inhibit initiation of protein synthesis
 Cause dissociation of polysomes into non-functional monosomes
 Blocking the initiation of protein synthesis  Initiation step (need many things to
come together @ 5’- 3’ end of mRNA)  30s, 50s, Proteins, mRNA, fmet (formyl)
 Ribosome attach via 5’  Streptomycin binds, stalling translation hindering
movement down the mRNA; Lost of fidelity
 Decrease Drug Uptake or Accumulation by altering porin channels in outer
membrane  Cannot be acquired, usually developed
 Active efflux (extrusion of toxic substances and antibiotics outside the cell)  Can
be acquired
 Alter ability of drug to cross the cytoplasmic membrane  Results from changes
in membrane proteins and alterations in regulation of genes in anaerobic
respiratory pathway
 Energy-dependent process tied into ETC and cell respiration
 O2-Dependent Process
 This is why AGs NOT active against anaerobes
 Three types of Aminoglycoside Modifying Enzymes (AME)  Bifunctional
 AG O-Phosphotransferases (APH) = Kinase; Any OH grp can be modified
 AG O-Nucleotidyltransferases (ANT) = eg. AMP, Causes steric bulk
 AG N-Acetyltransferases (AAC) = Any NH2 can be acetylated
 Streptomycin = 1
st
AG Discovered  Site of Action for AG on Bacterial Ribosomes affecting Protein Biosynthesis (Mycin=Streptomyces; Micin=Micromonospora)
Class Generic Name Brand Name PO IV Gram (+) Gram (–) Treatment Note Class Properties
Gentamycin Family
Gentamicin Garamycin Top/IV X P. aeruginosa; Burn, CF Coadmin w/ β-Lactam = syngery Basic/charged at
neutral pH
Highly H2O Soluble
Pretty toxic:
Nephro/Ototoxic
Netilmicin Netromycin X X Pink Eye Ethyl grp reduce inact. by AME
Kanamycin Family
Kanamycin Kantrex X X X Dysentery; MDR-TB Mixture of Kanamycin A
Amikacin Amikin X X Gent/Tobr Resist; Myco 50% potent, less prone by AME
Tobramycin Nebcin X X P. aerug, not Myco (TB) Use with antipseudo β-Lactam
Neomycin Family
Neomycin Mycifradin PO/Top/IV X X Burns Most nephrotoxic
Paromomycin Humatin X X X Ameobic Dysentery Tx: Leshmaniasis (Parasidic-Fly)
END OF MODULE 5
 Bacteria  Miscellaneous Information on Gram Stains
Bacterium Name Gram (+) Gram (–) Bacterium Name Gram (+) Gram (–)
Staphylococcus aureus  MSSA, MRSA X Streptomyces X
Pseudomonas aeruginosa X Enterobacteriaceae X
Mycobacterium tuberculosis Weak Acinetobacter X
Escherichia coli X Haemophilus influenzae X
Enterococcus  VRE X Neisseria gonorrhoeae X
Streptococcus pneumoniae X Actinomycetes X
Clostridium difficile X Coagulase Negative Staphylococci (CoNS) X

5. « Tetracycline Antibiotics »
Mechanism of Action Mechanism of Resistance
 Inhibit protein synthesis by binding to the 16S rRNA of the 30S ribosomal subunit
 6 TC binding sites on 30S Ribosome
 Block binding of the aminoacyl-tRNA to the ribosome
 Prevents elongation of peptide chain
 Reversible and bacteriostatic
 Selective toxicity results from … (Seldomly used due to toxicity)
 Poor penetration of mammalian cells and low affinity for mammalian
ribosomes (80S ribosome) will disrupt mitochondria protein synthesis (70S)
 Some bacteria will concentrate these drugs in the cell
 Binding of TC to 16S rRNA of 30S Ribo  Mg bridges drug-target like Bacitracin
 Pi-Pi stacking interaction with D-ring with C1054
 No effects on efflux pumps…?
 Enzymatic Inactivation – Rare, Tet X minooxygenase put OH on TC ↓ activity NOT
in any pathogen, 1 example of O-Acetyl Transferase
 Target Modification – Rare, Cl058G mutation ↓ Binding
 Energy-Dependent Efflux – ATP-required efflux pump actively transport drug out
of cell before reaching effective (60%) concentration and protein synthesis halted
 Ribosomal Protection Proteins (RPP) – Found in G+/- species and some
mycobacteria, on a chromosome or on a plasmid; resistance only at low TC conc.
Relates to elongation factors (GTPases) required in protein synthesis EF-Tu & EF-G
 Tet (O) and Tet (M) bind to ribosome in GTP-dependent manner and induce
dissociation of TC/Ribo complex  Protein Synthesis continues
 RPP  free the ribo from TC bound at Tet-1 site = free drug can still bind to
other sites; 6 Tet sites on a ribosome  reason its effective in low TC Conc
 Protein Synthesis Inhibitors  Effective against many organisms resistant to agents acting on the cell wall
Class Generic Name Brand Name PO IV G(+) G(–) Treatment Note
Old
Generation
Chlortetracycline Aureomycin Topical X X Gold color; Misused/Overused; Precursor for other TC; Photosensitivity C7
Tetracycline Achromycin V X X X H. Pylori Combo w/ Bismuth & Metronidazole; High Plasma conc, Long Duration
Oxytetracycline Terramycin X X X Note C6 difference  OH and CH3 Combined to form
Doxycycline via [H]
Methacycline Rondomycin X X Note C6 difference  CH2 double bond
Doxycycline Vibramycin X X X X Lack C6 OH; Decrease Ca2 Binding; Retains Mg Binding
Minocycline Minocin X X X X Dimethylamine C7; No C6 OH; Best absorbed; Longest T1/2
New Gen. Tigecycline Tygacil X X X MRSA & Anaerobe Add’l Contact w/ 16s rRNA; Not efflux pump; Active Tet-res bac; 5x bind aff.
« Tetracycline Extra Information »
General Features SAR
 C6 OH can degrade via acid/base  C4 center can epimerize in weak acid ↓active
 Coord (Chelates) w/ Metal Ions (Mg, Ca, Fe, Al) required for entry to G(-) cells
 Mg required to pass through porinrelease periplasmicapo-formchelates
 a-Stereochemical Config important for activity (AC4a)
 Removal of dimethylamine reduces activity (AC4)
 Keto-Enol system in proximity to D-Ring is important for activity (AC1/CC11)
 Basic Nitrogen of glycyl unit is essential (DC9)
 Must retain linear fused ring system must be six-membered and purely carbocyclic
 Targets for chelation with Divalent cations (Both; AC12a)
Contraindications and Side Effects
 If taken with dairy products, many of these agents are poorly absorbed
 Ca and Mg forms an insoluble complex  CI: Anti-acid
 Combo of broad spectrum of activity and poor absorption lead to superinfections
 Candida, Clostridum  Opportunistic Infections
 Tetracycline/Ca2+ complex can be deposited in teeth and bone during gestation
and early childhood  Not for pregnant women to use
 Small percentage of patients develop photosensitivity (UV Absorptive=C7 Halogen)
pKa1
pKa2
Three ionizable
groups and exist
as zwitterions at
neutral pH
Amphoteric = A salt
react with either
acid or base
pKa3

6. « Macrolide Antibiotics »
Mechanism of Action Mechanism of Resistance
 Reversibly bind to the 50S bacterial ribosomal subunit  Specifically 23S rRNA
 Inhibit translocation of the growing protein chain (Elongation)  A-P Site move
 Selective toxicity is achieved because these agents do not bind to mammalian
ribosomes (80S at therapeutic concentration
 Usually bacteriostatic  Stops replication
 Drug binds to polypeptide exit tunnel (Blocking) of bacterial 50S ribosomal subunit
 Intrinsic resistance in Gram-(-) organisms is probably due to impermeability of outer
membrane to the hydrophobic macrolides
 Acquired resistance involves three mechanisms
Target Modification  resistance mechanism found in the antibiotic producer
 Posttranscriptional methylation of 23S rRNA (A2058)
 Cross Resistance to Macrolides, Lincosamides and Streptogramin B-type
 MLS resistance phenotype  Also Resistance to azalides
 Erythromycin Resistance Methylase (erm) genes  Erm A most common
 Can be chromosomal or plasmid encodes (Transmittable)
 This mechanism accounts for almost all resistant isolates in clinical practice
Drug Inactivation (Inactive Kinase)
 Erythromycin esterases type I and II  hydrolyzes the lactone to a linear chain
 Macrolide 2’-phosphotransferase  Phosphorylates the 2’-OH of desosamine 
Analogous to AG PPT
Active efflux  ATP- dependent drug efflux pump reported for S. epidermidis
General Information
 Natural antibiotics (Polyketide)  Characerized by Large Cyclic Esters (Lactone):14
 Cladinose and Desosamine, may be attached
 Ring is highly functionalized (Me/OH)  Role in acid degradation in GI disturbance
 Complex stereochemistry; Aminosugar, Neutral sugar, Ketone
 Spectrum is similar to Penicillins (Gram +) and safe but with limited Hepatoxicity
 Can be used when patient is sensitive to pencillins
 Unstable in pH ≤4 Weak bases (Salt formulation); intramolecular rearrangement
 Protein Synthesis Inhibitors  Effective against many organisms resistant to agents acting on the cell wall
Class Generic Name Brand Name PO IV G(+) G(–) Treatment Note
1
st
Generation
(Erythromycin)
Erythromycin A X X X Ear Infections Acid Labile; Very Bitter; Salts and Ester prodrug ↑ Bioavailability and ↓ Bitter
Stearate Ethril X X Stearate Salt  18C saturated FA; Free base liberated in alkaline duodenum
Ethyl Succinate Pediamycin X X 2’ OH of Desosamine is esterified with ES, absorbed as ester then hydrolyzed
Estolate Ilosone X X Same as above w/ Propionate Ester; Lauryl Sulfate Salt (12C sat); Acid Stable
2
nd
Generation
(Derived from
Erythromycin)
Clarithromycin Biaxin X X X Disseminate MAC MAC  Birds/Humans; Acid Stable (C6); Legionella (G-); Rapid 1
st
Pass (14-OH)
Azithromycin Zithromax X X X Gonrrhea Azalide (N); Acid Stable (No Ketone); High Tissue Conc  2 binding site on 23S
Roxithromycin Rulid X X X Soft Tissue Infect Methoxyethoxymethyl eher of EryA Oxime; Better in vivo; Absp/Dist superior
Dirithromycin Dynabac Not In US Market Prodrug of Erythromycyclamine; Product of reduce EryA oxime, Imp Acid Stable
Telithromycin Ketek X X X Com-Acq-Pneum 1
st
Ketolide  No induce resistance (Mask); QD dosing, Acid Stable; Mya-Gravis
 Others Affecting Protein Biosynthesis
Class Generic Name Brand Name PO IV G(+) G(–) Treatment Note
Lincosamides
Clindamycin Cleocin X X Staph Infection in
Bones and Joints
Usually not DOC; Active metabolites (N-demethyl) and Sulfoxide; Can lead to
Fatal form of Colitis; Superinfection resistant producing Clostridium
Lincomycin Lincocin X X
MoASame as macrolides  23S rRNA of 50S ribosome MoRSame as macrolides (ErmA MLS Phenotype); Drug medication O-Nucleotidyl Xase
Oxazolidinones Linezolid Zyvox X X X X MRSA / VRE Reserved Uses; Inhibitors MAO reversible nonselective; Mainly Gram Positive
MoAOverall Distrupt protein syn, Bind 23S rRNA n ear interfeace w/ 30S; Block 70S MoRPoint Mutation 23S rRNA; G2576T changes to Uracil No binding; No X-Resist
Old Drug Chloramphenicol Chloromycetin X X X X Empirical Tx Overused; Penetrate BBB; Active vs anaerobes; BONE MARROW TOX, ↑aff 70S
MoABlock binding of Aminoacyl-tRNA, Inhibit peptide bond; Compete Macrolide Site MoRX-Resist, Ery/Linco/Strep  Methylation (MLS Resist); Alteration acetylate CAT
Protein Inhibitor Retapmulin Altabax Topical X Imeptigo (MSSA) Affect the protein;-static/↑*-cidal]; Fungus; Used in Vet (Swine); No X-Resist
MoAAct at Ribosomal Protein L3; Block P site, Inhibit Peptidyl Transfer; Prevent active MoRMutation at Ribosomal L3; Presences of Efflux; Hydrolase will destroy Ester

7. « Fluoroquinolones Antibiotics »
Mechanism of Action Mechanism of Resistance
 Disrupt DNA Replication/function (Folding and wadding)  Usually Bactericidal
 Targets TWO topoisomerases (II-Gyrase and IV) = Controls coiling, topological
 DNA Gyrase Relaxes AND supercoil DNA  ATP-dependent process
 Topo IV is a DECATENATING (Unties) enzyme  Unknot bring up DNA links
 Some FQ inhibits both of these, some just one
 Gyrase and Topo IV bind to double stranded DNA and they break both strands
 FQs bind and trap the intermediate in which the topoisomerase subunits are
covalently bound to broken DNA.  Bacteriostatic?
 Release of fragmented chromosome correlates with cell death  generate ROS
 Quinolones only recognize and bind the topoisomerase-DNA complex
 Selective toxicity: mammalian cells don’t have DNA gyrase and quinolones have
low affinity of for mammalian topoisomerase II
 Mutations in gyrase and topo IV genes – nearly always chromosomal mutation
 Arise from point mutation in gyrA, gene that codes for DNA gyrase subunit A
 parC and parE mutants are resistant, but less common
 Genes that encode the subunits of topoisomerase IV
 Decreased intracellular accumulation of the drug
 Modifications of membrane proteins Efflux Pumps
 In some S. aureus, the recG gene product can repair fluoroquinolone damage
 Plasmid-borne fluoroquinolone resistance (Transferable)
 Qnr proteins  Interfere with quinolone binding to gyrase and topoisomerase IV
 Proposed to recognize gyrase/topo IV and alter DNA binding properties
 Fluoroquinoline-modifying enzymes
 An aminoglycoside acetyltransferase (AAC(6’)-Ib) has mutated to modify
cipro- and norfloxacin  Bifunctional – it will still modify AGs
 Efflux pumps  The plasmid-encoded pump QepA can increase MIC by 10-fold
Side Effects and Toxicity
 Affects Cartilage, rupture tendon/Tendonitis, OT Prolongation, Photosensitivity
 Inhibitors of Nucleic Acid Metabolism and Function FQs  Cross-Resistance is often seen
Class Generic Name Brand Name PO IV G(+) G(–) Treatment Note
1
st
Gen. Nalidixic Acid Neggram X X Uncomplicated UTI Non-Fluroinated, Resistance widespread, Limited spectrum; Strong acid
2
nd
Generation
Nofloxacin Noroxin X X X UTI / Others Fluroquinolone; 100x more potent and broader spectrum; Widely used
Ciprofloxacin Cipro X X X UTI / Others Better absorption; Potent vs Pseudomonas; Safe; Bacillus Anthracis
Oflxacin Floxin X X X Mycobacteria;
Leprosy / TB
S-isomer most active; 8-125x difference in potency; High CSF concentration
Levofloxacin Levaquin X X X X
3
rd
Generation
Sparfloxacin Zagam X X X CAP Potent vs strep/anaerobes; Difluro; T1/2=18hrs; Low photosensitivity
Gatifloxacin Tequin X X X X Withdrawn Cause blood sugar fluctuation (Stim insulin secretion); Kidney/Liver Failure
4
th
Generation
Moxifloxacin Avelox X X X X Tuberculosis Bactericidal; Lower resistances; Not metabolized by P450; Inhibit Topo II/IV
Gemifloxacin Factive X X X CAP/AECB Potent inhibitor of TOPO IV and GYRASE in vitro; in vivo Gyrase perferred
« FQs Structure Activity Relationships »
 Position 2 should be unsubstituted
 N-1 must have a small alkyl group attached (Methyl, Ethyl, Cyclopropyl)
 N can replace C at position 8 without loss of activity (Nalidixic Acid)
 Groups at C-5 and position 8 can affect photosensitivity side effects
 Fluorine at C-6 increases activity
 Substituents at C-7 often increase activity
 Piperazine extends spectrum to include Ps. Aeruginosa
 Type of substituent can affect selective toxicity

8. « Antifolate Agents »
Mechanism of Action Mechanism of Resistance
 Coenzymes for biological processes  Synthesis of thymidine and purines and AA
 Specifically – sulfonamides are competitive inhibitors of dihydropteroate synthase
 Resemblance to p-aminobenzoic acid (PABA)
 Serve as inhibitor OR alternate substrates for DHPS
 Replace PABA in the condensation reaction catalyzed by DHPS – the result is a
 dihydropteroate derivative that cannot be further transformed to tetrahydrofolate
 Inhibition of DHPS causes bacteriostasis
Selective Toxicity
 It is a vitamin required in mammalian diets  mammals do not synthesize folate
 Bacteria cannot use folate from mammalian diet to replace depleted levels
 Because bacteria have a de novo biosynthetic pathway for folate most have not
developed transport systems for importing folate from the environment.
 Sulfonamides – major limitation to their use
 Organism overproduces PABA (Mutational)
 Acquired resistance from a plasmid-encoded DHPS that binds PABA normally
but has very low affinity for sulfonamides
 Alterations that decreased permeability of the cell  ↓Access (Mut Dev)
 Co-trimoxazole – less frequent but still observed
 Over 12 plasmid-borne genes expressing resistant DHFR variations are known
examples of a chromosomal DHFR with lowered trimethoprim affinity
 Also find elevated DHPS and/or DHFR levels in some resistant bacteria (↑*Target+)
SAR / General Features
 Sulfonamide NH is acidic  Allowing it to tightly bind (pKa 5-10, useful at 6-7)
 High pKa can cause crystallizein kidney (pH 6); Left Aniline NH2 is essential, R1=H
 Sulfonamide Inhibition of Folic Acid Biosynthesis  Inhibitors of Bacterial Cell Metabolism
Class Generic Name Brand Name PO IV G(+) G(–) Treatment Note
Prontosil
Sulfisoxazole Gantrisin X X X UTI Most Acidic pKa=5; R2=Dimethylisoxazole; Bitter; Acetyl=Hydro in GI; Pediazole
Sulfamethoxazole Gantanol X X X UTI pKa=6  Long T1/2~8hrs; Combine w/ TRIMETHOPRIM synergy  Septra/Bactrim
 Others No real Class or MoA
Generic Name Brand Name PO IV G(+) G(–) Treatment Side Effects Note
Phosphomycin Monurol X X UTI No X-Resist not SE Phosphonate; Bactericidal vs E.coil/E.faecium; Static vs others species; Salt
MoA Inhibits MurA (UDP-GlcNAc enoylpyruval transferase) – catalyzes 1st committed step in cell wall biosynthesis  covalently binds to Cys115 in the MurA active site
MoR fosA=Mn2+dept metalloglutathione transferase & fosB =catalyzes cysteine and Mg2+-dept & fosX=Mg2+-dept fosfomycin-specific epoxide hydrolase
Mupirocin Bactroban Topical X Skin Infection Mimics Ile(Isoleucine) Binds to ATP binding site, Bacteriostatic; -cidal=low pH
MoA Inhibits Protein synthesis via Bacterial Isoleucine tRNA (IleRS) blocking MoR Low-level=Nontransferable due to chromosomal mutation; High=insens
Novobiocin Albamycin Topical X MRSA AminocoumarinWarfarin like could possibly replace it in future; Polyketide
MoA Inhibits DNA Gyrase (Different from FQ, greater affinity for it); Specifically inhibit ATP Hydrolysis in GyrB  No energy required for inducing supercoiling
Metronidazole Flagyl X X X X Bacterial
Vaginosis
Urine Red/Brown,
Cancer, Select Tox
Tx: Paraistic infections  Trichomoniasis and GI ; Access GI, Bactericidal,
Active against Obligate anaerobic bugs, Antiprotozoan
Tinidazole Tindamax X X X X
MoA Nitro Group goes 1e- reduction; PFOR reduces ferredoxin; DNA/Protein damage MoR Resist to plasmid-borne gene encodes Nitroductase  Amino=inactive
Fosmidomycin Malaria In clinical Trials; Can be antibacterial; Phosphonate structure
MoA Inhibits Isoprenoid biosynthesis (Via DXR in non-mevalonate pathway AKA MEP synthase), prevent formation of Sterols, Ubiq, transporter, etc  HMG-CoA pathway

9. « Anti-Tubercular Agents »
Tuberculosis Information Tuberculosis Resistance
 Contagious airborne disease caused by Mycobacterium tuberculosis (Mtb); 1-3 cells
 Typically affects lungs (Spread via human to human contacts (Seem on X-Ray)
 Mtb=Latent TB (DormantNon-Replicating), Hard to treat
 Complex outer membrane (a barrier that is denseWax-like)
 Very slow growing (15-18hrs)  Long Therapy; Longer for resistant cases
 Reducing the spread of TB  Direct Observe Therapy Short course (DOTS)
 Multidrug Resistant Mtb (MDR-TB) = Resistant to BOTH Isoniazid and Rifampin
 Add 2
nd
Line injectable AG or Tuberactinomycin, and FQ
 Extensively Drug Resistant Mtb (XDR-TB) = Resistant to Isoniazid AND Rifampin
PLUS FQ AND at least an injectable 2
nd
Class Generic Name Brand Name PO IV G(+) G(–) Side Effects/Tx Note
1
st
Line Isoniazid Nydrazid X X Hepatotox (N-Ace) Static vs Resting  Cidal vs Dividing; Very Selective(Host no target); Low Tox
MoA Targets the InhA in mycolic acid synthesisKatG Ox N-NRadical+NADH=AdductInhibits InhA MoRLoss of Permiability (↓access); Mutation in InhA (target alter)
1
st
Line
(Rifamycins
Derivative)
Rifampin Rifadin X X X Tx: TB and MRSA Active vs Dividing/Semidormant-sterile; Moisture sensitive-Hydrozone; CNS
Rifapentine Priftin X X GINausea;
Discoloration Body
Fluid (Orange/Pink)
Cyclopentyl Derivative; Less freq dosing All Rifamycins Strong P450
inducers; ↑Protease Inhibitor
Metabolism; Bactericidal
Rifabutin Mycobutin X X Tx: MAC; Less P450 actions; Prophylactic
Rifaximin Xifaxan X X Tx: Traveler Diarrhea; <1% orally absorbed
MoA Inhibits bacterial DNA-dependent RNA polymerase (β-Subunit)Blocks Elongation, prevent gene expression; ALLOSTERIC inhibitor; Chelates Zn/Mg; No effect on mam
1
st
Line
Ethambutol Myambutol X X Visual Acuity, Color Static vs Dividing; Synergistic w/ Rifampin; (+)Isomer potent; Fish tank/hand
MoA Inhibits Mtb formation of cell wall arabinan; Interfere w/ arabinose acceptor MoRResults from acquisition of genes of Emb proteins (Dev Mut)
Pyrazinamide Aldinamide X X Gout Good vs Dormant/Semidormant; Acidic Environment; FA Synthase1/activate
2
nd
Line
(AGs)
Streptomycin Streptomycin X X
Renal, Neural (Oto)
Toxicity
Bactericidal Kill TB outside of macrophages (Limited window of attack);
Resistance due to Phosphorylation (APH); No effect vs MAC
Kanamycin Kantrex X X X
Amikacin Amikin X X
2
nd
Line
Ethionamide Trecator SC X X X GI Upset / NV Less potent, well distributed; Req Oxidative Activation (KatG) ethA gene
Cycloserine Seromycin X X X CNS Toxicity MoA Block conversion of L-Ala to D-Ala (Inhibits Alanine Racemase); No X
Aminosalicyclic Acid PAS Parasal X X X GI Upset (Acid) MoAAntifolat; Competitive inhibitor of Mycobacterial DHPS; Spec; Static
Capreomycin Capastat X X X Renal, CNVIII Toxic Tuberactinomycin Abx; Highly basic, AG like SE (Oto); Resist=Lost of function
MoA Interferes w/ Initiation of tRNA(Fidelity) and Elongation16S rRNA by AG w/ contacts 23S rRNA MoRDrug Mod (Ace/Pho); Target Mod (rRNA OMT)
2
nd
Line (FQs)
Levofloxacin Levaquin X X X X Tx: Mycobacteria;
TB
S-isomer most active; 8-125x difference in potency; High CSF concentration
Moxifloxacin Avelox X X X X Bactericidal; Lower resistances; Not metabolized by P450; Inhibit Topo II/IV
Experimental
Agents
Nitroimidazopyran PA-824 Under
Development
Affects Lipid/Protein Synthesis; Block late state of mycolic acids; Cidal both
Diarylquinoline R207910 Long T1/2; Comb w/ INH, RIF, PZA; No X-resist; atpE geneProton Pumps
« Anti-Fungal Agents »
Amphotericin Mechanism of Action General Anti-Fungal information
 Amphotericin B complexes with ergosterol in the fungal membranes to form pores
 Permitting K+ and Mg2+ to escape  Shuts down protein and DNA Synthesis
 Ergosterol is unique to fungi (Selective Toxicity)
 Ergosterol is similar enough to cholesterol structure that selectivity is not complete
 Results in toxicity, especially in the kidney
 Takes 8 AmpB molecule + 16 sterol to form HALF a poreneeds 2 HALVES for pore
 Fungi are eukaryotic=more complex; harder to treat Abx has no effect on fungi
 Share host features ie: Protein and Nucleic Acid synthesis (Drug blocks)
 Ergosterol Synthesis  Azoles, Allylamines, Morpholines
 NA Synthesis/Functions  5-Fluorocytosine • Chitin Synthesis  Nikkomycin
 Spindle Distruption/Antimitosis  Griseofulvin • Protein Synthesis  Sordarins
 Membrane Distruption  Polyenes • Glucan Synthesis  Echinochandins

10.  AmphotericinsAgents Taken Systemically to Treat Systemic Mycoses (Fungal Infections) …Anti-Fungal Continues
Class Generic Name Brand Name PO IV Cidal Treatment Side Effects Note
Amphotericin B Fungizone X Yes Crytococcus Gattii Kidney Damage Gold Standard; Dose dependent; Shake n’ Bake; Amphoterrible
Lipid
Formulation
Lipid Complex Abelcet X Yes Not 1
st
line; Treat
Invasive fungal
infections
ABLC; Ribbon-like configuration; Decrease free drug = ↓ Toxicity
Colloidal Dispersion Amphocil X Yes ABCD; Disk-like (Cholesteryl Sulfate); ↑ incidence of Hypoxia/Chills
Liposomal Ambisome X Yes Tx: Crytococcus LAMB; True Liposome (Spherical); ↑Conc in plasma=long duration
 Enchinocandins Affects the Exterior of Cells  Cell Walls
Class Generic Name Brand Name PO IV Cidal Treatment Side Effects Note
Lipopeptide
Antifungals
Caspofungin Cancidas X Yes Invas.Aspergillosis Minimal Tx: Candida/Pneumocystis; Active vs Azole-Resist Strain; Acetylation
MoA Inhibits 1,3-β-Glycan Synthase = Block assembly of fungal cell wall MoR Rare; Subsitution in Fks1p Subunit of 1,3-β-Glycan Synthase ↓susceptibility
Micafungin Mycamine X Candidiasis Broad Spectrum; Prophylactic uses w/ AIDS pts; Active Azole-Resist
Anidulafungin Eraxis X Candidiasis Tx: esophageal/candidemia/peritonitis; Lipophilic; Terphenyl Tail
Flucytosine (5-FC) Ancobon X Usually in combo w/ Amphotericin B; Synthetic; Requires Activation
MoA Interferes w/ Fungal Protein/DNA Synthesis (5-FCF-FU + FdUMP (Phos) dUMP + TS = dTMP & FdUMP blocks TS); 5-FC  FUMP  5-FU = No Protein
 Azoles Anti-Fungals Mostly Triazoles or Imidazoles  No Antibacterial Actions (Target Not Present) and Concentration Dependent at Site of Infection
Mechanism of Action Mechanism of Resistance
 Overall= Disrupt Ergosterol SynthesisSpecifically=Inhibit Sterol C14a-demethylase
 Disruption=Lack of ergosterol (Downstream) for membrane function and fluidity
 Results in a build-up of C14-methylated sterols (Toxic=Ignosterol) that get into the
cell membrane and lead to faulty function and leakage of cell contents
 Ianosterol  Zymosterol via C-14 DeMEase via CYP51A1 (Oxidative) block by Azoles
 Reduced intracellular accumulation of drugs, due to either decreased uptake or
increased efflux
 Altered (Mut) sterol C-14 demethylase or other ergosterol biosynthetic enzymes
 Amplification of genes encoding for target enzymes  ↑Target Concentration
 All been identified in isolates of Candida obtained from pts failing azole therapy
Class Generic Name Brand Name PO IV Cidal Treatment Side Effects Note
Imidazole Ketoconazole Nizoral X Terato, Steroid P450 Inhibitor=Steroid Imbalance; Toxic=N-deactylate; Best low pH
Triazole Fluconazole Diflucan X X Cryto Meningitis Better than Keto Tx: Oral/Esoph Candida & Pulmonary Cryto; Good Absorp/Dist+CSF
Dubbed 2
nd
Keto Itraconazole Sporanox X X Fungal Infection Better; Liver Fail 1
st
DOC; Case of liver failure and ↓Cardiac Contraction Force (Rare)
New Generation
Triazoles
Voriconazole Vfend X X Invas.Aspergillosis Visual/↑Liver Enz Outperformed AmpB in trials; 30% pts=Visual Disturbance (30min)
Posaconazole Noxafil X Broader Spectrum and Better activity than Itraconazole
Ravuconazole Phase 3 Trials Long T1/2 OD Dosing; Similar to Fluconazole but with Thiazole
 Agents Taken Systemically to Treat Non-Systemic Mycoses (Fungal Infections)
Class Generic Name Brand Name PO IV Cidal Treatment Side Effects Note
Older Agents
Griseofulvin Fulvacin X No Hair/Nail Infection HA, Rash, GI Pain Fungistatic; Poor oral bioavailbility (Micronized increase it)
MoA Inhibits fungal mitosis by preventing separation of chromosomes  Blocks normal microtubule functions (Selective Toxicity unclear)
Terbinafine Lamisil PO/Top Warts Liver Failure Allyl Amine; Concentrates in Stratum Corneum
MoA Inhibits Esgosterol Biosynthesis  Targets Squalene-2,3-Epoxidase (Don’t make epoxide); Squalene (Epoxidase) Epoxide
Butenafine Mentax Topical Yes Dermatophytes Exerts Anti-Inflammatory in vivo; ↑Conc remains for prolong time
Thiocarbamates
Tolnaftate Tinactin Topical Ath. Foot/Jock Itch Allyl Amine; Inhibits squalene 2,3-epoxidase
Naftifine Naftin Topical Jock Itch/Ringworm Allyl Amine
New Agents
Amorolfine Loceryl Topical Dermatophytes In solution (Lacquer); water-insoluble; Penetrate=↑Conc; Slow Cl
MoA Two-Steps: Morpholine derivative that inhibits fungal sterol ∆14 reductase and sterol ∆7-8 isomerase (Zymosterol [Inh]Intermed.[Inh]Ergosterol)
END OF MODULE 6