Biochemistry of Antibiotic Resistance

The site of the World Health Organization describes antimicrobial resistance as “Antimicrobial resistance (AMR) is resistance of a microorganism to an antimicrobial medicine to which it was previously sensitive. Resistant organisms (they include bacteria, viruses and some parasites) are able to withstand attack by antimicrobial medicines, such as antibiotics, antivirals, and antimalarials, so that standard treatments become ineffective and infections persist and may spread to others. AMR is a consequence of the use, particularly the misuse, of antimicrobial medicines and develops when a microorganism mutates or acquires a resistance gene.” About 440,000 new cases of multidrug-resistant tuberculosis (MDR-TB) emerge annually, causing at least 150,000 deaths worldwide. Drug-resistant tuberculosis (XDR-TB) has been reported in 64 countries till mid of year 2012 (WHO 2012).

Bacterial resistance is a serious concern in the treatment of infectious disease. Effectiveness of antibacterial agent remains very good in the beginning of its introduction. However, as the use of antibacterial compound increases, pathogens develop resistance to it making the compound ineffective. In fact, pathogens acquire resistance to most of the antibacterial compounds very easily, thus creating need for new sources and more antimicrobial agents.

Bacteria develop resistance to antibacterial agents either due to their inherent characteristics, genetically encoded in its DNA, or acquire it from mutation in the host DNA or through encoded extra chromosomal materials in a horizontal transfer process. Several mechanisms have evolved which confer microbes with antimicrobial resistance. Four main mechanisms which confer antimicrobial resistance are (1) enzymatic inactivation of the antimicrobial molecules by the enzymes produced by bacteria, (2) reducing the affinity of the antimicrobial compound to the target by modifications, (3) efflux of the antibiotic from the cell through membraneassociated pumping proteins, and (4) resistance acquired through mutation or horizontal transfer.

Inactivation of Antimicrobial Agent

Antimicrobial molecules may be inactivated by either direct destruction or modification by enzymes synthesized by bacteria that selectively target and destroy the activity of the compound. There are three main mechanisms through which antimicrobial molecules may get deactivated: enzymatic hydrolysis, group transfer, or redox process. Many antimicrobial molecules have hydrolytically susceptible chemical bonds which are essential for their antimicrobial activity. Certain enzymes target and cleave these bonds and destroy antimicrobial activity of the compound. Bacteria produce such enzymes which require only water as a co-substrate which leads to inactivation of the antimicrobial molecules (Wright 2005). Some enzymes can induce resistance by modifying the antimicrobial molecules by chemical substitution or addition of acetyl groups to the periphery of the antibiotic molecule. This modifies the structure of the antimicrobial molecule causing poor antibiotic–bacteria interaction. Some bacteria metabolize antibiotics by oxidation and reduction mechanisms to detoxify and resist antibiotic effects.

 
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