PROCESSES OF ANTIMICROBIAL RESISTANCE

PROCESSES OF ANTIMICROBIAL RESISTANCE


Over eighty years ago Alexander Flemming discovered penicillin, and since then a multitude of natural and synthetic agents have been developed in our humankind fight against microorganisms, which comprise three main groups: bacteria, fungi and viruses. Antibiotic or antibacterial agents are selective poisons with activity only against bacteria, not viruses or fungi, since other specific agents kill these microbes selectively.

Antibiotics are the naturally occurring entities such as penicillins, while the term antimicrobial encompasses a range of synthetic agents like quinolon, as well as naturally derived ones. The key consideration of antimicrobial agents is their mode of action against bacteria. A typical bacterial cell antimicrobial and identify which sites certain antimicrobial agents act upon. Irrespective of their shape or size, this fundamental cellular structure permits certain generalizations.

Additionally the structure and composition of the cell wall, i.e. whether it is gram positive or gram negative, has a bearing on how effectively an antimicrobial agents can penetrate the bacterial cell. One way of viewing the role of antimicrobial agents and their selective responses to bacteria is by way of comparison to battlefield. In essence there are :
(1) The bacterial soft spots, or targets; key targets are cell wall, protein and DNA synthesis, substituent biosynthetic pathways.
(2) Our weapons, or antimicrobial agents; the various antimicrobial agents attack the different key target sites.
(3) The enemy’s response, or the ways of bacterial defense.

What processes of antimicrobial resistance are expressed by these gene sequences ? Basically there are four main mechanisms by which these processes occur; 1. Drug inactivation (enzyme inactivation), 2. Cellular access (decreased permeability), 3. Site modification (altered target site), 4. Biochemical Feedback (by pass). The main mechanisms of antimicrobial resistance processes are illustrated on the figure below; modified from Schentag JJ, 1999, (Operation Resistance 2000; The Terrain, Dynamics and Defense of Antimicrobial Resistance, Sheffield Dawson Publisher Ltd, 3-16).


A. DRUG INACTIVATION (enzyme inactivation)
The mechanism is a process by which bacterial enzymes either completely destroy the antimicrobial, or modify the drug by adding a molecule to it and rendering it incapable of specific activity. Examples of these two activities are β-lactamase; which destroy the β-lactam ring, the acetylation of chloramphenicol, the modification of aminoglycoside by acetylation or other additions.

B. CELLULAR ACCESS (decreased permeability)
The mechanism is controlled in terms of allowing entry to the bacterial cell, or an active process of ejecting drugs via an efflux pump. Coincidental with these processes is intrinsic resistance due to physical barriers – e.q. Gram-negative outer membrane provides resistance to some β-lactams.
Efflux pump mechanisms are increasingly recognized as a common method by which bacteria can remove a wide range of antimicrobials, from tetracyclines to quinolones.

C. SITE MODIFICATION (altered target site)
Site modification – involves alteration of the target site of an antimicrobial agent so that the fit is no longer sufficient to exert activity. Analogous to a lock and key situation, wherein a small change in the lock can render the key useless; a good example would be the alteration of the 23s ribosome to prevent macrolides, such as clarithromycin, from binding to the ribosome.

D. BIOCHEMICAL FEEDBACK (by pass)
Biochemical feedback – via target hyperproduction is best represented by the folic acids pathway in which an organism may deliberately over-produce an enzyme so as to saturate all the sulfonamide or trimethoprim present and still be able to catalyze the biosynthetic pathway.


See other contains :
1. Antimicrobial Resistance
2. Resistance Mechanism and Their Genetic Bases
3. Factors That Encourage the Spread of (Antimicrobial) Resistance