TARGETED THERAPIES
26 Novel Targets of Antimicrobial Therapies
SARAH E. MADDOCKS
INTRODUCTION: TRADITIONAL TREATMENTS AND CLASSICAL TARGETS
During the golden age of antibiotic discovery, from the 1930s through the 1960s, methods of antibiotic identification relied solely on scientific observation, and while chemical analogues such as amoxicillin, derived from penicillin, continued to be developed, they retained the same mechanisms of action and hence the same bacterial targets. Moreover, there are finite modifications that can ultimately be made to âoldâ classes of antibiotics. Consequently, only two new classes of antibiotics have been discovered in the past 40 years, and both entered the market early in the new millennium. The advent of the genomics revolution offered a new hope for the discovery of novel antimicrobial targets. Genomic strategies were utilized to identify potential antibacterial targets, namely those that, if inhibited, resulted in the death of the bacterium. Such targets were to be present in pathogenic strains of bacteria and absent from the human host; they could include metabolic pathways, receptor ligands, and virulence traits, to name a few. Despite the abundance of targets identified using this strategy, no new antibiotics have reached the marketplace as a result of the genomics approach. However, new antimicrobials with novel targets continue to be identified and contribute to the ongoing struggle against antimicrobial resistance that threatens to return humankind to a situation comparable to the preantibiotic era.
This article will describe and discuss some of the novel targets for emerging antimicrobial treatments, highlighting pivotal research on which our ability to continue to successfully treat bacterial infection relies.
COMBINATION APPROACHES TO TACKLE MULTIDRUG-RESISTANT BACTERIA
Combination therapies are widely used in medicine and have proved crucial for the treatment of infectious diseases, including, for example, Mycobacterium tuberculosis, which is treated using four simultaneously administered antibiotics. Monotherapies are increasingly inadequate, and several strategies are currently employed that combine either different classes of antibiotics or antibiotics with targeted adjuvants. Above all, the principal aim of this approach is to reduce the minimum inhibitory concentration or to resensitize resistant organisms. Often this involves inhibition of different targets within the same synthetic or metabolic pathways, inhibition of the same target within different pathways, or inhibition of unrelated targets within different pathways. One such example is the commercially available antibiotic combination co-amoxiclav, which utilizes a combination of amoxicillin, a beta-lactam antibiotic, with the beta-lactamase inhibitor clavulanic acid, which renders beta-lactamase-producing microorganisms susceptible to the action of the penicillin-derived antibiotic (1).
Antibiotics combined with adjuvants in this manner have increased efficacy, but the adjuvant itself is generally not bactericidal; this approach reduces the onset of antimicrobial resistance but does not affect a new cellular target per se. Two-component sensorâregulator proteins are ubiquitous among prokaryotes but, despite their high degree of conservation, are not essential for viability. As such, they have become attractive targets for adjuvants, especially due to the predominant role many of these systems have in antimicrobial resistance. Cell wall biosynthesis in Staphylococcus aureus is in part regulated by the VraSR system, which coordinates the expression of d-alanyl-d-lactate, a peptide that is incorporated into peptidoglycan (2). Additionally, VraSR also mediates resistance to beta-lactam and glycopeptide antibiotics; as such, expression of this system is induced by exposure to beta-lactams, glycopeptide, and bacitracin. Null-mutations of vraSR result in greatly enhanced susceptibility to antibiotics that disrupt cell wall biosynthesis, similarly if vraSR expression is inhibited resistance is also lessened (3, 4).
Natural and synthetic two-component inhibitors exist, and the RWJ-family and its derivatives are the best characterized. These inhibitors are hydrophobic tyramines which exhibit a broad spectrum of activity against Gram-positive microorganisms and are themselves inherently bactericidal (5). Analogues vary in their ability to inhibit bacterial growth, a characteristic that has been correlated with an ability to âjamâ two-component systems. Mechanistically, such inhibitors appear to function by impairing auto-phosphorylation of sensor kinases, sometimes completely abolishing this function. Compounds are thought to disrupt the four-helix bundles required for dimerization, driving them apart to expose hydrophobic residues that result in misfolding or aggregation, with a subsequent loss of function. Synthetic two-component inhibitors are also known for Gram-negative microorganisms; for Pseudomonas aeruginosa, inhibition of the AlgR1R2 system results in reduced expression of alginate biosynthesis genes, but inhibitions of two-component sensor-regulators are not directly antimicrobial (6). It is supposed that inhibitors of this natur...