Treating MRSA and Other Difficult Bacterial Infections

Typically, an antibiotic will kill or disable a bacterium by preventing the organism from synthesizing or utilizing an essential molecule or structure that is essential for survival. Common targets are the bacterial cell wall (beta-lactams, vancomycin), ribosomal protein synthesis (macrolides, tetracy- clines), DNA replication (fluoroquinolones), and folate synthesis (TMS.)

Bacteria have evolved many ways to reduce the effectiveness of antibiotics. There are four common mechanisms: enzymatic degradation, reduction of intrabacterial con- centration, alternate synthetic pathways, and target modification.

Enzymatic degradation of antimicrobials is typified by betalactamases produced by many bacteria. The large number of available betalactam drugs demonstrates the methods that can be used to overcome this mechanism. New “generations” of cephalosporins are created which are resistant to degradation. Alternatively, enzyme inhibitors are developed which inactivate the enzymes, “restoring” clinical effectiveness.

Reduction of drug concentration inside the target organism occurs in two ways: the bacterium increases the barrier between the internal milieu and the outside world, or it actively removes drug with efflux pumps. Such efflux- mediated resistance is often very broad, excluding multiple types of antibiotics and biocides.

Metabolic changes are common mechanisms mediating resistance to, for example, sulfonamides. Some bacteria overproduce PABA, which, by sheer statistical effect, prevents saturation of the folate synthesis pathway. Plasmodium strains have evolved the ability to salvage folate very efficiently, allowing them to multiply even when unable to synthesize folate de novo.  [...]