UNIT IV:

ANTIMICROBIAL
DRUGS
Topics up Aheaad!

• History of Chemotheraphy

• Spectrum of activity

• Action of antimicrobial drugs

• Tests to guide chemotherapy

HISTORY OF CHEMOTHERAPY
Father of Modern Chemotherapy

PAUL EHRLICH
Coined the term “chemotherapy”
Can you remember???

• What is the hypothetical drug speculated

by Paul Ehrlich to kill harmful
microorganism without damaging the
host cells??
Father of antibiotics
ALEXANDER FLEMING
Identified the mold
Penicillium notatum that
inhibit the growth of S.
aureus
The discovery of sulfadrugs
GERHARD DOMAGK
Discovered “Prontosil”
- a sulfanilamide containing
dye
FLOREY & CHAIN
- Develop penicillin
- used a more prolific strain from
Penicillium chrysogenum
Spectrum of Antimicrobial
activity
Narrow-spectrum vs. Broad-spectrum
NARROW-spectrum
- kill a much smaller range of microorganism
- example: Pen G affects gram positive but very few gram
negatives
BROAD-spectrum
- inhibit a broader range of groups of microorganisms.
Narrow-spectrum vs. Broad-spectrum
• A primary factor involved in the selective toxicity of antibacterial
action lies in the lipopolysaccharide outer layer of gram negative
bacteria and the porins that form water-filled channels across this
layer
• Drugs that pass through the porin channels must be relatively small
and preferably hydrophilic. Drugs that are lipophilic (having an affinity
for lipids) or especially large do not enter gram-negative bacteria
readily.
What microorganism does bacitracin is
synthesized from?
• Usually a broad-spectrum antibiotic is used in treating disease
• Disadvantage: it also destroys certain organisms in the microbial flora.
• If the antibiotic does not destroy certain organisms in the normal
microbiota but does destroy their competitors, the survivors may
flourish and become opportunistic pathogens
Some medically important terms
• SUPERINFECTION - growth of a target pathogen that has developed
resistance to the antibiotic.
• BACTERICIDAL - kill microbes directly
• BACTERIOSTATIC - prevent microbes from growing
Action of antimicrobial drugs
1. Inhibition of cell wall synthesis
• antibiotics prevent the synthesis
of intact peptidoglycan

• weakening of the cell wall

• Lysis (cell death) NOTE

Because antibiotics only
targets the synthesis
process, ONLY ACTIVELY
GROWING cells are
affected.
2. Inhibiting protein sythesis

This accounts for the selective toxicity of some

antibiotics
3. Injuring the plasma membrane
• changes in the permeability of • loss of important metabolites
the plasma membrane from the microbial cell
4. Inhibiting Nucleic Acid Synthesis
• interfere with the processes of DNA replication and transcription in
microorganisms.
• Some drugs with this mode of action have an extremely limited
usefulness because they interfere with mammalian DNA and RNA as
well.
5. Inhibiting the synthesis
of essential metabolites
•Inhibits particular enzymatic activities
Antibacterial antibiotics
For antibiotics to function as a “magic bullet,” they usually must
target microbial structures or functions that are not shared with
mammalian structures or functions
Inhibitors of cell wall synthesis
1. Penicillin
• Natural penicillins
• Isoxazolyl Penicillins/Anti-staphylococcal
• Aminopenicillins or Extended-spectrum
Antibiotics (w/ G-)
• Anti-pseudomonal penicillins
1. Penicillin
• All penicillin structure contain
beta-lactam ring called the
nucleus
• Prevent the cross-linking of the
peptidoglycans, which interferes
with the final stages of the
construction of the cell walls,
primarily of gram-positive
bacteria
Natural penicillins
• Narrow spectrum, against gram positive bacteria
• DOC for staphylococci, streptococci, spirochetes
• Probenecid (antigout, uricosuric) – compete w/ excretion of Pen to
decrease drug clearance;
Natural penicillins
Pen V • Side effects:
• Phenoxymethylpenicillin • Hypersensitivity
• PO (sa vivig) • GI upset
Pen G
• Benzylpenicillin
• IV (ini-inGect)
Benzathine Pen G
• IM increases absorption
DISADVANTAGE

• Narrow spectrum of activity and susceptibility to penicillinases.

• Penicillinases are enzymes produced by many bacteria, most notably

Staphylococcus species, that cleave the β-lactam ring of the penicillin

molecule. Because of this characteristic, penicillinases are sometimes

called β-lactamases.
Isoxazolyl Penicillins/Anti-staphylococcal
• Very narrow spectrum – for Staphylococcus only
• Prev. Tx w/ Pen
• β-lactamase resistant or penicillinase-resistant
Isoxazolyl Penicillins/Anti-staphylococcal
• Methicillin (Prototype) – Nephrotoxicity and
interstitial nephritis upon withdrawal
• Nafcillin – causes Neutropenia
• Oxacillin
• Cloxacillin, Dicloxacillin
• Fludocillin
Extended-spectrum penicillins

• effective against many gram-negative bacteria as well as gram-

positive ones, although they are not resistant to penicillinases.

• Aminopenicillins (Ampicillin, and Amoxicillin)

• Carboxypenicillin (Carbenicillin, and ticarcillin)

Given if px. is resistant to aminopenicillin. Additional activity to Pseudomonas

• UREIDOPENICILLIN: Mezlocillin, and Azlocillin (Broader spectrum)

Aminopenicillins or Extended spectrum
antibiotics (with G- activity)
• Added spectrum – G(-)
• E. coli, Listeria, Proteus, Haemophilus
• Moraxella catarrhalis

Are aminopenicillins β-lactamase resistant?

e.g. Ampicillin + Sulbactam (Unasyn)
Antipseudomonal penicillins
• Carboxypenicillin;
• Carbenicillin, Ticarcillin
• Piperacillin,
• Mezlocillin, Azlocillin withdrawn from market
• Piptaz = piperacillin + tazobactam
• Timetin = ticarcillin + clavulanate

Side effects: Blood dyscrasias

Penicillins Plus β-Lactamase Inhibitors

• CO-AMOXICLAV
(Amoxicillin +
Clauvulanic acid)
Penicillins Plus β-Lactamase Inhibitors
AMOXICILLIN CLAVULANIC ACID
2. β-lactam antibiotics

A. CARBAPENEMS
• Bind to penicillin-binding proteins (PBPs) which are
involved in cross linking/transpeptidation of
peptidoglycan layer thus inhibiting peptidoglycan layer
cross linking/transpeptidation in cell wall
•Side effects:
• CNS toxicity: seizure, and encephalitis due to
BBB permeability
2. β-lactam antibiotics
A. CARBAPENEMS
substitute a carbon atom for a sulfur atom and add a double
bond to the penicillin nucleus. BROAD SPECTRUM
Only used on life-threatening infections (reserved)
- Imipenem - active against hospital acquired infection
- Doripenem - P. aeruginosa infection
- Ertapenem, Doripenem
2. β-lactam antibiotics
B. MONOBACTAMS
• Single ring instead of a conventional double β-lactam ring
• Has an L ring
• No action on G+
• Toxicity: Vertigo, skin rash, hepatoxicity
- Aztreonam - low toxicity, affects only certain gram-negative
bacteria, including pseudomonads and E. coli.

• Advantage: no sulfur moiety = no cross-activity w/ Pens & Cephs = no

hypersensitivity rxn similar to pens and cephs
Cephalosporins
1st generation Cephalosporins
• “Ceph” except Cefazolin and • Active against gram positive
Cefadroxil cocci (staph and strep)
• Cephalothin • Side effects: Phlebitis
• Cephalexin
• Cephradine
• Cephapirin
 2nd generation Cephalosporins
• “Cef” except Loracarbef • Cefamandole
• None in “-ime”/”-one” • Cefmetazole
except Cefuroxime • Cefoxitin
• Same with 1st gen + HEN • Cefotetan
• Haemophilus
• Cefaclor
• Enterobacter
• Neisseria • Cefonicid
• Cefprozil
 2nd generation Cephalosporins
• SIDE EFFECTS: • Cefamandole
• Disulfiram like • Cefmetazole
reaction: • Cefoxitin
• Cefamandole • Cefotetan
• Cefotetan • Cefaclor
• Cefmetazole • Cefonicid
• Cefprozil
 3rd generation Cephalosporins
• “Cef” except Moxalactam • Cefixime
• Ends in “-ime”/”-one” except • Cefpodoxime
Cefdinir, Ceftibutin, • Cefotaxime
Cefditoren
• Ceftizoxime
• Against Pseudomonas,
Bacteroides • Ceftazidime
• Cefoperazone –
disulfiram like reaction
• Ceftriaxone
 4th generation 5th generation
cephalosporins cephalosporins

• Wide coverage: G (–) and G • Same side effects with 4th

(+) gen
• General side effects: • Ceftobipirole
• Nausea
• Ceftaroline
• Vomiting
• Ceftaroline fosamil (prodrug)
• Diarrhea
– only ceph active against
• Cefepime MRSA & MRSE
• Cefpirome
Beta-lactamase inhibitors
β-lactamase producing organisms
• Streptococcus, E. coli, H.
influenzae • Clavulanic acid
• PPNG (penicillin-producing N.
gonorrhea) • Sulbactam
• Resistant N. gonorrhea
• Tx: Spectinomycin
• Tazobactam
• Toxicity: Cholestatic jaundice
3. Polypeptide antibiotics
A. BACITRACIN (Mixed polypeptide)
• Effective primarily against gram-positive bacteria, such as
staphylococci and streptococci
• Inhibits the synthesis of cell walls at an earlier stage than penicillins
and cephalosporins.
• Topical application due to its high nephrotoxicity in oral
administration
Glycopeptide Antibiotics
VANCOMYCIN
• Bind to D-Ala-D-Ala terminus of the peptidoglycan layer = will no
longer cross-link
• Derived from a species of Streptomyces found in the jungles of
Borneo (Streptomyces orientalis)
• Treatment of Staphylococcus aureus infections that are resistant to
Methicillin
Glycopeptide Antibiotics
VANCOMYCIN
Toxicity:
• Nephrotoxicity
• Ototoxicity
• Red man syndrome
Release of PG
Tx: NSAID or slow IV
Prophylaxis: diphenhydramine
Cycloserine
• Drug-resistant tuberculosis
• Block incorporation of D-Ala into the
peptidoglycan side chain
• CNS toxicity
Antimycobacterial Antibiotics
1. ISONIAZID (INH)
- very effective synthetic antimicrobial drug against
mycobacterium tuberculosis.
MOA: inhibit the synthesis of mycolic acids
- administered simultaneously with rifampin or ethambutol.
To minimize resistance

Because the tubercle bacillus is usually found only within

macrophages or walled off in tissue, any antitubercular drug
must be able to penetrate into such sites.
2. ETHAMBUTOL
- effective only against mycobacteria
- inhibits incorporation of mycolic acid into the cell wall.
- use as the secondary drug to avoid resistance problems
What is the source of Penicillin used by
Florey and Chain?
What are the first line
drugs used to treat
tuberculosis?
Protein synthesis inhibitor
1. CHLORAMPHENICOL
inhibits the formation of 50S portion of the 70S prokaryotic
ribosome
- broad spectrum, low cost
- ADR: suppression of bone marrow activity
- Toxicity: Gray baby syndrome

Physicians are advised not to use the drug for trivial conditions or ones
for which suitable alternatives are available.
2. AMINOGLYCOSIDES
interfere by changing the shape of the 30S portion of the
70S prokaryotic ribosome.
- best-known aminoglycoside is streptomycin
ADR: Nephrotoxicity, Vestibulocochlear toxicity (8th cranial
nerve damage), Ototoxicity,
AMINOGLYCOSIDES
• Gentamicin and Tobramycin • Amikacin
• -micin: from Micromonospora • Narrowest therapeutic
• -mycin: from Streptomyces index
• (prototype: Streptomycin) • Most ototoxic
• MOA:
• Inhibit initiation complex
• Cause mRNA misreading
• Inhibit translocation
AMINOGLYCOSIDES
Streptomycin
• Tx. Of TB, Zoonoses
(Tularemia), Brucellosis,
Plague (Yersinia pestis)
• Toxicity: Congenital deafness
(CI to pregnant women)
Neomycin
• Hepatic encephalopathy
• Overproduction of
ammonia in the body
Spectinomycin
• Tx. Of resistant strains
of N. gonorrhea
3. TETRACYCLINES
- Interfere with the attachment of the tRNA carrying the amino
acids to the ribosome at the 30S portion of the 70S ribosome
- They do not interfere with mammalian ribosomes because they
do not penetrate very well into intact mammalian cells.
- Broadest spectrum against anaerobes

ADR:
• Brittle bones
• Contraindicated to pregnant
• Tooth enamel dysplasia for children under 8 y.o
• Photosensitivity (demeclocycline)
Tetracyclines
• Doxycycline
• Prophylaxis for leptospirosis
• Tx. Of malaria
• Minocycline (most potent)
• Tigecycline (broadest spectrum)
• Demeclocycline
• Methacycline
• Oxytetracycline
5. MACROLIDES
- named for the presence of a macrocyclic lactone ring
- frequent alternative drug to penicillin.
- binds to 50s ribosomal subunit
ADR: QT prolongation (Torsades de pointes)

1. Erythromycin (former Ilocin)

Alternative for px allergic to B-lactam antibiotic
2. Azithromycin (high distribution to tissues)
Once a day dosing
3. Clarithromycin (methylated erythromycin)
More effective for staph and strep infections
5. MACROLIDES
- named for the presence of a macrocyclic lactone ring
- frequent alternative drug to penicillin.
- binds to 50s ribosomal subunit
ADR: QT prolongation (Torsades de pointes)

1. Erythromycin (former Ilocin)

Alternative for px allergic to B-lactam antibiotic
2. Azithromycin (high distribution to tissues)
Once a day dosing
3. Clarithromycin (methylated erythromycin)
More effective for staph and strep infections
6. STREPTOGRAMINS
- block protein synthesis by attaching to the 50S portion of the
ribosome, as do other antibiotics such as chloramphenicol.

dalfopristin- blocks an early step in protein synthesis

quinopristin - blocks the later step in protein synthesis
Use together

The combination causes incomplete peptide chains to be released and is

synergistic in its action
- FOR GRAM POSITIVE BACTERIA THAT ARE RESISTANT TO ANTIBIOTICS
7. OXAZOLIDINEDIONES
- developed in response to vancomycin resistance
- inhibit the binding at 50S ribosomal subunit close to the point
where it interfaces with the 30S subunit.

Linezolid (Zyvox) - treatment for MRSA & VRSA

7. OXAZOLIDINEDIONES
- developed in response to vancomycin resistance
- inhibit the binding at 50S ribosomal subunit close to the point
where it interfaces with the 30S subunit.

Linezolid (Zyvox) - treatment for MRSA & VRSA

8. PLEUROMUTILINS
- Originally a product of the Pleurotis mutilus mushroom, most
are now semisynthetic derivatives.

Mutilin
Retpamutilin
9. LINCOSAMIDES
• Tx: Pneumocystis jerovicii/carinii pneumonia
• Inhibits 50s ribosomal sub-unit
• ADR:
• Skin rash (w/ sulfur)
• Neutropenia
• Pseudomembraneous colitis (Clindamycin)
• DOC: metronidazole

• Anaerobic infection treatment:

• Above the diaphragm: Clindamycin
• Below the diaphragm: Metronidazole
Injury to plasma membrane
• The synthesis of bacterial plasma membranes requires the synthesis
of fatty acids as building blocks. Researchers in search of an
attractive target for new antibiotics have focused their attention on
this metabolic step, which is distinct from the fatty acid biosynthesis
in humans. Interference with this process is the basis of several
antibiotics and antimicrobials. A weakness in this approach, however,
is that many bacterial pathogens are able to take up fatty acids from
serum. In the soil environment from which the antibiotic-producing
streptomycetes were isolated, fatty acids are not available. Examples
of successful antimicrobials that target fatty acid synthesis are the
tuberculosis drug isoniazid and the household antibacterial triclosan
1. LIPOPEPTIDES
daptomycin
MOA: Attack the membrane of the bacterial cell. This
results in structural changes in the membrane, followed by
arrest of the synthesis of DNA, RNA, and protein— rapidly
killing the bacteria
- treatment of MRSA infection
Polymyxin B
- topical treatment of superficial infections
 Competitive Inhibitors
of the Synthesis
of Essential Metabolites
 E
TNOTE de
N O a
s m lls
Interferons:n s : e i n ce l
o t st ra
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Signaling ro ho made ve
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Int naling ase b to s
and release by host cells
Sig rele nse
nd espo to several
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Anti-fungal
drugs
Where is ergosterol found?