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. ß-lactam antibacterial agents

2. Other inhibitors of bacterial cell wall synthresis

B. Nucleotide synthesisC. 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. ß-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

Classificationa. Natural penicillins Penicillin G

b. Semisynthetics penicillins

Methicillin, oxacillin, cloxacillin, nafcillin, discloxacillin

c. Extended-spectrum penicillins (Broad-s)

a. Aminopenicillin: ampicillin, amoxycillin b. Carboxypenicillin: carbenicillin, ticarcillin c. Ureidopenicillins: azlocicllin d. Piperazine penicillin: piperacillin

Penicillins1. 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

2. Bacterial resistance ß-lactamases

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

4. Toxicity very limited

Cephalosporins

Classificationa. First-generation : Oral & injectible form

b. Second-generation : mostly injectible

c. Third-generation: mostly injectible

d. 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 synthesis1. 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 synthesis1. 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-spectrum2. 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 resistanceA. 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. Enzymatics inactivation

B. Modification of cell wall permiability

C. Alteration of target molecules

D. Development of alternate pathways

E. Active exclusion of the antimicrobial agent from the bacteria

F. Development of tolerance

A. Enzymatic inactivation of antibacterial agents

1. ß-lactamases: hydrolize ß-lactam ring of penicilin

2. Acetyltranferases, phosphorylases, nucleo-tidases: 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

4. Electron transports. Uptake aminoglycosides depens on electron transport to oxygen → this agents are not effective to anaerobic bacteria or to facultative organisms in anaerobic enviroment (e.g. abscess)

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 RESISTANCE MECHANISMS

Penicillin & Cephalosporin

Enzymatic inactivation (ß-lactamase)Target modification (PBPs)Tolerance

Sulfonamides Active exclusionTarget alternation

Aminoglycosides Enzymatic inactivation (acetyltrans-ferase, phosphorilase, nucleotidases)Target alteration (30S ribosomal unit)Decriaced cell wall permiability

Tetracyclines Active exclusion (mutation of membrane transport protein)

Chloramphenicol Enzymatic inactivation (acetyltrans-ferase)

Macrolides Target alteration (50S ribosomal unit)

Quinolones Target alteration (DNA gyrase mutation)