Lecture 01.2014

MBSM 713: BIOCHEMISTRY OF
ANTI MICROBIAL AGENTS
Lecture one
Dr. G. Kattam Maiyoh
01/23/15 1
GKM/KISIIU/MBSM713
/BIOC.AMIC.AGENS.LEC01

Importance of Microbes
• Life is microbial! (to the first
approximation)
– Micro-organisms colonise every
environment on earth
– >80% of life’s history was bacterial
– You have more bacterial cells than
human cells (10x more)
– Microbes play a key role in the
biosphere
– Pathogenic microbes globally are
the most important cause of human
disease and death
01/23/15 2GKM/KISIIU/MBSM713

Importance of Infection
• Has played a decisive role in history
• Still major cause of death and misery worldwide
• Examples of public anxieties
– Meningitis, Food poisoning
– Mad cow disease
– HIV
– Cholera
– Emerging infections e.g. Ebola, swine flu
– Hospital Infection (Nosocomial infections)
• Antibiotic-Resistant Superbugs

What are Antimicrobials???
• Antimicrobials are drugs that destroy microbes,
prevent their multiplication or growth, or
prevent their pathogenic action
– Differ in their physical, chemical, and
pharmacological properties
– Differ in antimicrobial spectrum of activity
– Differ in their mechanism of action

• It is chosen so that it kills the desired microbes
only, but not the cells in your (host) body.
• Each different type of antibiotic affects different
bacteria in different ways.
• For example, an antimicrobial might inhibit a
microbe’s ability to turn glucose into energy, or its
ability to construct its cell wall.
• Therefore the microbe dies instead of reproducing.
It is a selective poison

Classification of Antimicrobials
• Based against the target organism
– Antibacterial (antibiotics)
– Antifungal
– Antiviral
– Antiprotozoan
– Antihelminthics

History of Antimicrobials
• Mostly on antibiotics
• (anti, "against"; bios, "life") An antibiotic is a
chemical substance produced by one organism that
is destructive to another.
• The word antibiotic came from the word antibiosis
a term coined in 1889 by Louis Pasteur's student
Paul Vuillemin which means a process by which
life could be used to destroy life.

Ancient History
• The ancient Egyptians, the Chinese, and
Indians of central America all used molds to
treat infected wounds.
• However, they did not understand the
connection of the antibacterial properties of
mold and the treatment of diseases.
Mould

Late 1800s
• The search for antibiotics began in the late
1800s, with the growing acceptance of the
germ theory of disease, a theory which
linked bacteria and other microbes to the
causation of a variety of ailments.
• As a result, scientists began to devote time
to searching for drugs that would kill these
disease-causing bacteria.

1871
• The surgeon Joseph Lister, began researching the
phenomenon that urine contaminated with mold would not
allow the successful growth of bacteria.
1890s
• German doctors, Rudolf Emmerich and Oscar Low were
the first to make an effective medication that they called
pyocyanase from microbes.
• It was the first antibiotic to be used in hospitals. However,
the drug often did not work
• Learning check – why do you think the drug did not work
some of the time?

1928: Fleming and Penicillin
Sir Alexander Fleming observed that colonies of the bacterium
Staphylococcus aureus could be destroyed by the mold
Penicillium notatum, demonstrating antibacterial properties.

1935- the first sulfa drug discovered
•German pathologist and bacteriologist
Credited with the discovery of
Sulfonamidochrysoidine (KI-730) – the
first commercially available antibacterial
antibiotic (marketed under the brand
name Prontosil)
•1939 Nobel Prize in Physiology/
Medicine
Gerhard Domagk
(1895–1964).

•1940 – Howard Florey and Ernst Chain
performed first clinical trials of penicillin.
•1942
•Invented manufacturing process for
Penicillin G Procaine.
•Penicillin could now be sold as a drug.
•Fleming, Florey, and Chain shared the
1945 Nobel Prize for medicine for their
work on penicillin.
Howard Florey
(1898–1968)

Penicillin in summary
• Penicillin was isolated in 1939.
• Concerted effort by a number of scientists;
• Originally noticed by a French medical student,
Ernest Duchesne, in 1896
• Re-discovered by bacteriologist Alexander
Fleming – Published investigations in 1929
• Dorothy discoved the molecular layout of
penicillin – used x-rays
• 1939 Dr. Howard Florey demonstrate penicillin's
ability to kill infectious bacteria.
• 1940_____________________________
• 1942 _____________________________

1943
•American microbiologist
made the drug streptomycin
from soil bacteria, the first of
a new class of drugs called
aminoglycosides.
•Streptomycin could treat
diseases like tuberculosis,
however;
•The side effects were
often too severe.
Selman Waksman (1888–1973)

1955
Tetracycline was patented by Lloyd Conover,
which became the most prescribed broad
spectrum antibiotic in the United States.
1957
•Nystatin was patented and used to cure
many disfiguring and disabling fungal
infections.
•Invented by Elizabeth Lee Hazen and
Rachel Fuller Brown
•Researchers for the New York Department
of Health
01/23/15 17GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC01

1981
•SmithKline Beecham patented
Amoxicillin or moxicillin/clavulanate
potassium tablets.
•First sold the antibiotic in 1998
under the trade names of Amoxicillin,
Amoxil, and Trimox.
•Amoxicillin is a semisynthetic
antibiotic.

Definitions
• Chemotherapy The use of drugs to treat a
disease
• Antimicrobial drugs Interfere with the growth of
microbes within a host
• Antibiotic Substance produced by a
microbe that, in small amounts,
inhibits another microbe
• Selective toxicity A drug’s ability to kills harmful
microbes without damaging the
host
• Bacteriostatic/ Modes of action that either kill or
bacteriocidal inhibit growth of bacteria
• Spectrum of activity Range of effect within or between
groups of microbes; narrow vs.
broad-spectrum01/23/15 19GKM/KISIIU/MBSM713

Static vs. Cidal
•The graphs show the growth curves for a
bacterium treated with two drugs.
•The upper curve shows the activity of a
bacteriostatic drug.
•The bacterial growth resumes when the
drug is withdrawn.
•The cidal drug, shown in the lower graph,
kills bacteria from the time of administration
to the culture.
• Penicillins, aminoglycoside,
vanconmycin, bacitracin , the
polymyxin, and colistin are
bactericidal.
• Tetracyline , Fusidic acid ,
Macrolides, Sulfonamides and
sulfones on the other hand, are
bacteriostatic.

Classification of Antibiotics
• Bacteriostatic vs. Bactericidal

Principles of antimicrobial use!
01/23/15 GKM/KISIIU/MBSM713
22

1. Identification of the Infective Organisms1. Identification of the Infective Organisms
History
taking
Physical
examination
Laboratory

History TakingHistory Taking
• Duration of
fever
• Associated
symptoms:
Systematic
review
• History of
treatment
• Underlying
diseases and
• Traveling
• Pets
• Vaccination
and drug
prophylaxis
• Illness in
family
• Diseases
outbreak01/23/15 24GKM/KISIIU/MBSM713

Physical ExaminationPhysical Examination

Laboratory Investigation in the Diagnosis of Infectious AgentsLaboratory Investigation in the Diagnosis of Infectious Agents
Mandell, Douglas, and Bennett’s Principle and Practice of Infectio

2) Antimicrobial susceptibility
– Appropriate specimen collection and transport
– Disk diffusion susceptibility testing
– Minimal inhibitory
concentration (MIC)

Underlying diseases
Drug allergy
Pregnancy/Breast feeding
Age
Genetic or Metabolic
abnormalities
Sites of infection
Immune status
Hepatic and renal function
3) Determine host Factors3) Determine host Factors

4) Antimicrobial Factors4) Antimicrobial Factors
Spectrum
Mechanisms
of action
Pharmacokine
tic
Pharmacodyn
amic
Drug
interaction
Side effect
Drug
monitoring

Indications for AntimicrobialIndications for Antimicrobial
Combinations TherapyCombinations Therapy
Prevention of the emergence
of resistant organisms
Polymicrobial infections
Empirical therapy
As narrow as possible, as
broad as necessary
Synergistic/Additive activity01/23/15 31GKM/KISIIU/MBSM713

Disadvantages of Inappropriate Use ofDisadvantages of Inappropriate Use of
Antimicrobial CombinationsAntimicrobial Combinations
Antagonism
Superinfection
Cost
Adverse effects

Reasons for Treatment FailureReasons for Treatment Failure
Delay in diagnosis or
therapy
Wrong or incomplete
diagnosis
No infection
Nonbacterial infection (for
antibiotics)
Polymicrobial infection
Errors in susceptibility
testing
Decreased activity at site

Inadequate concentration
of antibiotic at the site of
infection
Improper dose
Decreased absorption from
food or drug interaction
Increased elimination of
agent
High protein binding
Poor delivery (eg. shock,

Impaired immune
defenses
Development of drug
resistance
Superinfection
Other host factors
Necrotic tissue
Foreign body

A major cause of
antimicrobial overuse is
“treatment”
of contaminated cultures or
colonization.
Use Antimicrobials WiselyUse Antimicrobials Wisely
Treat infection, NOT
contamination or
colonization
Use local data
Know your local antibiogram
Know your patient population
ll infections need antimicrobial t
http://www.cdc.gov

• When infection is
cured
• When cultures are
negative and
infection is unlikely
• When infection is
not diagnosed
Use AntimicrobialsUse Antimicrobials
WiselyWisely
Stop antimicrobial
treatment
http://www.cdc.gov

Mechanisms of Action of Antibacterials
– Protein synthesis inhibitors
– Cell wall synthesis inhibitors
– Plasma membrane-injuring agents
– Nucleic acid inhibitors
– Metabolic/enzyme inhibitors

The Action of Antimicrobial Drugs
Figure 20.2

Protein Synthesis Inhibitors
Figure 20.4

Figure 20.2

• Penicillins
– Natural penicillins: G, V
– Semisynthetic penicillins
• “-cillin “ suffix
• Carbapenems
• Monobactam
Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis: e.g Penicilins

Penicillins
Figure 20.6

• Cephalosporins
– 2nd
, 3rd
, and 4th
generations more
effective against
gram-negatives
Inhibitors of Cell Wall Synthesis: Cephalosporins
Figure 20.9

• Polypeptide antibiotics
– Bacitracin
• Topical application
• Against gram-positives
– Vancomycin
• Glycopeptide
• Important "last line"
against antibiotic resistant
S. aureus (e.g. MRSA)
Inhibitors of Cell Wall Synthesis: Polypeptides

• Antimycobacterium antibiotics
– Isoniazid (INH)
• Inhibits mycolic acid synthesis
– Ethambutol
• Inhibits incorporation of mycolic acid
Inhibitors of Cell Wall Synthesis: Anti-Mycobacterials

Figure 20.2

• Polymyxin B
– Topical
– Combined with bacitracin and neomycin in over-
the-counter preparation
Injury to the Plasma Membrane

Figure 20.2

• Rifamycin
– Inhibits RNA synthesis by RNA polymerase
– Antituberculosis
• Quinolones and fluoroquinolones
– Ciprofloxacin
– Inhibits DNA gyrase so blocks DNA polymerase
– Urinary tract infections
Inhibitors of Nucleic Acid Synthesis

Figure 20.2

– Sulfonamides (Sulfa drugs)
• Inhibit folic acid synthesis
• Broad spectrum
Competitive Inhibitors
Figure 5.7

Figure 20.13
TMZ - Trimethoprim + Sulfamethoxazole: Synergism

Thank for your attention
01/23/15 GKM/KISIIU/MBSM713
54

Lecture 01.2014

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