Objectives

Antimicrobial agents

At the end of the session students will be able to:

Define the terms: Antibiotics, antimicrobial agent, chemotherapeutic drug, antiseptics, broad spectrum antibiotics, selective toxicity. Describe the properties of a good antibiotic Explain the mechanism of action of antimicrobial agents List commonly used antibiotics and their advantages and disadvantages Explain the mechanism of antibiotic resistance

Definitions
Antibiotics Antimicrobial agent Chemotherapeutic drug Antiseptics Broad spectrum antibiotics Selective toxicity

Properties of a good antibiotic

The antimicrobial agent should:
Have strong activity against microorganism Have low toxicity Be least toxic to Be in its active form Achieve sufficient levels at Have least side effects on host Be cost effective easily available Be easily administered

Antimicrobial agents
Antimicrobial agents may be classified according to their mechanism of action or depending on whether they actually kill the bacteria
Bactericidal: Bacteriostatic:

Mechanism of action
Inhibition of cell wall synthesis Effecting cell membrane structure and function Inhibition of Inhibition of nucleic acid synthesis Inhibition of

Inhibition of cell wall synthesis

Cell wall is a prime target as mammal lack the cell wall while bacteria posses one Cell wall is mainly composed of ------------, the synthesis of which depends on specific integral enzymes Inactivating or interfering with these enzymes structurally or functionally destroys bacterial cell wall. Major class of antimicrobials that affect the bacterial cell wall are:

Lactams
Large family of antibiotics Structure:
4 member beta-lactam ring and a carboxyl group. Modifications of the basic structure allow for varying spectra of activity, from very narrow to very broad.

How lactams work:

Attacks the cell wall of bacteria which is made up with the help of enzymes known as PBPs bind to lactam antibiotics in growing bacteria and hence cell wall synthesis distrupted

Glycopeptides
Beta Lactam class
Penicillins

Examples
Penicillin Ampicillin Piperacillin Mezlocillin Cefazolin Cefuroxime Ceftriaxone Ceftazidime Aztreonam

Glycopeptides affect the second stage of cell wall synthesis - occurs before the formation of peptide bonds by inhibiting enzymes that are vital for continued formation of peptidoglycan Members in this group include:
Vancomycin Bacitracin

Cephalosporins

Monobactams

Carbapenams

Imipenam Meropenam

Narrow spectrum antibiotics, acts against gram positive bacterium

Effecting cell membrane structure and function

These antimicrobials have a limited spectrum of activity, and are quite toxic. They disrupt the cell membrane resulting in leakage of macromolecules and ions. Members in this group include:
Amphotericin Polyenes nystatin

Inhibitors of protein synthesis

Ribosome's of bacteria are very much different from those of mammalian cells, hence a good target point for antimicrobials to act Antibiotics binds to either 50s or 30s ribosomal subunits, and inhibits or kills the organism, depending on reversible or irreversible binding respectively
Members in this group of antibiotic are: Aminoglycosides Macrolides Chloramphenicol Clindamycin, etc

Polymyxins interact with phospholipids of the bacterial cell membrane, alters the permeability and osmotic integrity. They are mainly active against

Inhibition of nucleic acid synthesis

Two categories of antimicrobial agents interfere with DNA synthesis:

Inhibition of essential metabolites

Folic acid is necessary for bacterial DNA synthesis Bacteria make their own folic acid, as they cannot obtain this essential metabolite. Sulphonamides and trimethoprim competitively inhibit enzymes responsible for synthesis of folic acid These agents in combination gives a synergistic effect, and gives a very broad-spectrum of activity

Those that disrupt replication

Example: Nalidixic acid inhibits enzyme DNA Gyrase, which is essential for super coiling of DNA, and subsequently kills the bacteria.

Those that disrupt the final product of replication

Example:

Members in this group include:

Rifampicin Fusidic acid Quinolones

Antibiotic Resistance
Biological resistance:
changes in the organism that makes it less susceptible to a particular antimicrobial

Antibiotic Resistance

Clinical resistance:
when susceptibility lost to an extent that the drug is no longer effective

Environmentally mediated resistance:

results directly from physical or chemical characteristics of the environment, e.g.: pH, anaerobic atmosphere, cationic concentration

Antibiotic Resistance
Common pathways of antibiotic resistance:
Enzymatic destruction

Intrinsic resistance:
resistance resulting from normal genetic, structural or physiological state of an organism.

Acquired resistance:
Altered target resistance that result from altered cellular physiology and structure by changing an organisms usual genetic make-up. Resistance may be acquired by:
Genetic mutation Gene transfer mechanisms Combination of gene transfer and mutation.

Decreased uptake

Enzyme modification

Activity
For the following groups of antibiotics describe their mechanism of action, spectrum of activity, examples of antibiotics / antimicrobial agents within the group. Aminoglycosides Beta lactams Fluoroquinolones Glycopeptides Macrolides Polymixins

References
Delost, M. D 1997, Antimicrobial Susceptibility Testing, Introduction to Diagnostic Microbiology: A Text and Workbook,Mosby Inc., Missouri, pp 83 89. Forbes, B.A, Sahm, D.F, Weissfeld, A.S 2002, Principles of Antimicrobial Action and Resistance, Bailey & Scotts Diagnostic Microbiology, 10th Edition, Mosby Inc., Missouri, pp 234 249. Ray, C.G, Ryan, K.J, 2004, Sherris Medical Microbiology, 4th Edition, McGraw-Hill, USA, pp 193 227.