Antimicrobials

and their Mechanism of Action

 • Chemical substances that are
produced by microorganisms that has
the capacity to inhibit or kill other
microorganisms
• Can also be synthesized chemically
• May be classified as broad spectrum
Antibiotics or narrow spectrum
• May be classified as either natural,
semi-synthetic, or synthetic drugs
• May be either bacteriostatic or
bactericidal
 • Minimum-inhibitory concentration
(MIC) – the lowest concentration of a
drug that can inhibit bacterial growth
• Minimum-bactericidal concentration
(MBC) – the lowest concentration of a
drug that can still kill bacteria
Terminologies • Therapeutic index – ratio of toxic dose
to the therapeutic dose; the higher
the index, the more effective the
chemotherapeutic agent
Characteristics of
Antimicrobial Agents
• The agent must be in active form
• The agent mist be able to achieve
concentration at the site of
infection that is higher than the
pathogen’s MIC to be effective
• Must have selective toxicity
Types of Antimicrobial
Agents
1. Cell wall inhibitors
• Selective antibiotics with high therapeutic index
• Interferes with the biosynthesis of
peptidoglycan
• The beta-lactam antibiotics form covalent
complexes with enzymes that generate mature
peptidoglycan molecule (transpeptidase
enzymes that mediate peptidoglycan cross-
linking)
• The active component of the beta-lactam family
of drugs is the beta-lactam structure
• Glycopeptides inhibit cell wall synthesis by
binding to the end of the peptidoglycan,
preventing transpeptidation
Types of Antimicrobial
Agents
2. Inhibitors of Folate Synthesis
• The folic acid pathway provides essential
precursor molecules needed for DNA
biosynthesis
• Sulfamethoxazole/SMZ (a sulfonamide)
prevents the formation of dihydropteroate
through competitive inhibition of para-
aminobenzoic acid with the enzyme
dihydropteroate synthase
• Trimethoprim blocks the formation of the
tetrahydrofolate by inhibiting
dihydrofolate reductase
 3. Agents that interfere with DNA replication
• Topoisomerases I, II, III, and IV are necessary for DNA
replication
Types of • Quinolones affect DNA replication by targeting
topoisomerases II (DNA gyrase) in gram negative bacteria
Antimicrobia and Topoisomerase IV in gram-positive bacteria

4. Agents that interfere with DNA transcription

l Agents • Transcription of DNA into RNA is mediated by RNA
polymerase
• Rifampin targets the RNA polymerase subunit, blocking
RNA chain elongation
 5. Agents that inhibit protein synthesis
• Some antibiotics target the 30S ribosomal
subunit (aminoglycosides, spectinomycin,
Types of tetracyclines, glycylcyclines)
• Others target the 50S ribosomal subunit
Antimicrobia (macrolides, lincosamides, chloramphenicol,
oxazolidinones, streptogramins)
l Agents • Only aminoglycosides are bactericidal; the
rest are bacteriostatic
• Aminoglycosides, chloramphenicol, and
tetracycline have side effects
Bacterial Resistance to Antimicrobials

• Impermeability. Antibiotics must be able to penetrate the cell wall to reach

their targets.
• In gram negative bacteria, the negatively charged LPS functions as a
selectively permeable barrier against negatively charged antibiotics
• Porins serve as outer membrane channels that permit the influx of
nutrients and efflux of waste products.
• Efflux. Efflux pumps are found in bacteria and function as transporter
proteins for the extrusion of toxic substances and antibiotics from the
interior of the cell to the external environment
Bacterial Resistance to Antimicrobials

• Enzymatic inactivation. Bacteria can

produce enzymes that destroy
antimicrobial agents before they are able
to reach the targets
• This is commonly encountered in the
resistance against beta-lactam antibiotics
(all contains the beta-lactam ring structure)
• Beta-lactamases are enzymes that
hydrolyzes beta-lactams, preventing the
antibiotic’s ability to bind transpeptidase
enzymes
• The effect can be minimized by the use of
beta-lactamase inhibitors (clavulanic acid,
sulbactam, and tazobactam). These
inhibitors bind beta-lactamases and
reduces their detrimental effects on the
beta-lactam antibiotics
Bacterial Resistance to Antimicrobials

• Target site modification. Modification of a target can reduce the binding affinity of the antibiotic to
the target
• Quinolones target DNA gyrase (topoisomerase II) and topoisomerase IV, inhibiting DNA synthesis.
Resistance to quinolones are caused by mutations encoding amino acid changes in these DNA
topoisomerases
• Mutations may lead to alteration in transpeptidase enzymes , resulting to decreased affinity to
beta-lactam antibiotics
• Acquisition of new targets. Microorganisms become resistant by acquiring cellular targets with
reduced affinity for the antibiotic
• There is a gene that encodes for a new type of transpeptidase enzyme with reduced affinity for
beta-lactam antibiotics
• Sulfonamides compete with dihydropteroate synthase enzymes to block the formation of
nucleotide precursors. Some bacteria acquired a new enzyme that is unaffected by sulfonamides