Baedah Madjid BAGIAN MIKROBIOLOGI FK-UNHAS 2007

A. Antibiotics & antibacterial agent a. Antibiotics: Produced only by microorgnisms (Natural) b. Antibacterials: Produced: natural, synthetics or semi-synthetics B. Bacteriostatic agents & Bactericidal agents C. Narrow-spectrum & Broad-spectrum antibacterial agents D. MIC & MBC

1. Microorganism : a unique & vital target

susceptible to C must exist in microorganism, target must differ from related host target side effects

2. Antibacterial Agents
a. Able to penetrate the bacterial surface & reach target of its action. b. Can reach the infected tissue c. Can not diffuse in to mammalian cells

3. Host
a. Intact immune system
b. vascularization & drainage

Antibacterial agents that inhibit: A. Cell wall synthesis

1. -lactam antibacterial agents 2. Other inhibitors of bacterial cell wall synthresis

B. Nucleotide synthesis C. Nucleic acid synthesis

1. DNA synthesis inhibitors 2. RNA synthesis inhibitors

D. Protein synthesis
1. Inhibitors of the 30S ribosomal unit 2. Inhibitors of the 50S ribosomal unit

A. Antibacterial agents that inhibit cell wall synthesis

1. -lactam antibacterial agents
Inhibition of peptidoglican layer cross-linking: - Penicillin - Cephalosporin

- Others: carbapenems (e.g. imipenem), monobactam (e.g. aztreonam)

2. Other inhibitors
Inhibition of peptidoglican synthesis: - Cyclocerine - Vancomycin - Bacitracin

Penicillins
Classification
a. Natural penicillins
Penicillin G c. Extended-spectrum

penicillins (Broad-s)
a. Aminopenicillin: ampicillin, amoxycillin b. Carboxypenicillin: carbenicillin, ticarcillin c. Ureidopenicillins: azlocicllin d. Piperazine penicillin: piperacillin

b. Semisynthetics penicillins
Methicillin, oxacillin, cloxacillin, nafcillin, discloxacillin

Penicillins
1. Mechanism of action
Target:penicillin-binding proteins transpeptidase, carboxypeptidase, autolytic enzymes Inactivation of than enzymes rapid dest-ruction of peptidoglycan & dissulution cell wall bacterial lysis

3.

Spectrum
a. Natural Penicillin Narrow : Gr + & anaerob b. Semi-synthetics -lactam ring << < accessible c. Extended-spectrum P Gr+ & Gr Some: have -lactamase inhibitors

2.

Bacterial resistance
-lactamases

4.

Toxicity very limited

Cephalosporins
Classification
a. b. c. d. First-generation : Oral & injectible form Second-generation : mostly injectible Third-generation: mostly injectible Fourth-generation: mostly injectible

Spectrum: broad-spectrum Toxicity :

Allergy More toxic than penicillin nephrotoxic Latest generation < toxic than early-generation

B. Antibacterial agents that inhibit nucleotide synthesis

1. Sulfonamides
a. Preparations: Sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfaamethoidiazine orally. b. Mechanism of action: bacteriostatic conpetitive to PABA c. Spectrum: broad d. Toxicity: Hypersensitivity hematologic disorders & crystal formation

2. Trimethoprim structure = hydrofolic acid 3. Sulfamethoxazole-trimethoprim synergic

combination.

C. Antibacterial agents that inhibit nucleic acid synthesis

1. DNA synthesis inhibitors a. Novobiocin : limited clinical use b. Quinolones:
Nalidixic acid : brod spcetrum UT Flouroquinolones: cloxacin, ciprocloxacin derivate of naidixic acid , orally & parenterally.

c. Nitromidazoles, Metronidazole.
Spectrum: T. vaginalis, G. lamblia, E. histolytica, obligate anaerobic. Toxicity: mutagenic

2. RNA synthesis inhibitors Rifampicin : M. tbc, M. leprae, Legionella, meningitis (N. meningitidis, H. influenzae)

D. Antibacterial agents that inhibit Protein synthesis

1. Inhibitors of the 30S ribosomal unit a. Aminoglycosides - Streptomycin: 2nd line anti-tbc, injection - Neomycin: topical. orally - Kanamycin: primary used as anti-tbc - Gentamycin, tobramycin, amikasi, netilmycin: fewer bacteria R b. Tetracyclines: broad-spectrum 2. Inhibitors of the 50S ribosomal unit a. Chloramphenicol: typhoid fever, H. influenzae, rickettsia b. Macrolide antibiotics: erythromycin, azithromycin c. Lincosamides: lincomycin, clindamycin

Acquisition of bacteral resistance A. Intrinsic resistance

related to bacterial structure feature (permiability of bacterial cell wall) determined by chromosomal gene e.g. Pseudomonas aeroginosa.

B. Mutational resistance
related to chromosomal mutation unable to interact with antibacterial.

C. Acquisition of resistance genes

- Resistance ( R ) plasmids
- New chromosomal genes

Mechanisms of Bacterial Resistance

A. B. C. D. E. Enzymatics inactivation Modification of cell wall permiability Alteration of target molecules Development of alternate pathways Active exclusion of the antimicrobial agent from the bacteria F. Development of tolerance

A. Enzymatic inactivation of antibacterial agents

1. -lactamases: hydrolize -lactam ring of

penicilin

2. Acetyltranferases, phosphorylases, nucleotidases: modify aminoglycosides incapble of

binding to the ribosomal target.

3. Chloramphinecol acetyltransferases: similar

to aminoglycoside transferases.

B. Modification of cell wall permiability

Degree of cell wall permeability correlates w intrinsic resistance 1. Purin (specific outer membrane protein in Gr-negative) Mutation affecting purin inhibit transport >>> ab. 2. Lipopolisaccharida (LPS) inhibit passage of
hydrophobic antibacterial agents throuh the cell wall. Thus mutans which lack polysaccharide capsule and minimal LPS more permiable to multiple antibiotics

3. Membrane transport proteins. Mutation of mtp

resistance to tetracyclin as a result of transportation into cell electron transport to oxygen this agents are not effective to anaerobic bacteria or to facultative organisms in anaerobic enviroment (e.g. abscess)

4. Electron transports. Uptake aminoglycosides depens on

C. Alteration of target molecules. Molecule target

may be located on cytoplasmic (e.g. PBP), or inside the cytoplasic membrane (e.g. ribosome). Alteration of the target affnity for the antibacterial compound.

D. Development of alternate pathways. A

mutant enzyme may bypass the synthetic block exerted by antibiotic by using an alterntivepathway.

E. Active exclusion of the antimicrobial agent from the bacteria. R to tetracyclin is mediated by the
synthesis new transport proteins that actively exluded the drug.

F. Development of tolerance. Impermiability outer

membrane & inactivation of murein hydrolases (autolytic enzymes) renders bactericidal agent to bacteriostatic.

ANTIBACTERIAL
Penicillin Cephalosporin Sulfonamides Aminoglycosides

RESISTANCE MECHANISMS

& Enzymatic inactivation (-lactamase) Target modification (PBPs) Tolerance Active exclusion Target alternation Enzymatic inactivation (acetyltrans-ferase, phosphorilase, nucleotidases) Target alteration (30S ribosomal unit) Decriaced cell wall permiability Active exclusion protein) (mutation of membrane transport

Tetracyclines Chloramphenicol Macrolides

Enzymatic inactivation (acetyltrans-ferase) Target alteration (50S ribosomal unit)

Quinolones

Target alteration (DNA gyrase mutation)