Is there a future for FabI inhibitors as antibacterial agents? (2013)

The bacterial target FabI, enoyl-acyl carrier protein reductase (ENR), has stimulated considerable interest in the anti-infectives arena as a new fully validated target in all strains of Staphylococcus and the target for several potential anti microbial agents that may provide specific therapy for a very common and significant bacterial pathogen, Staphylococcus aureus, including MRSA. The widespread use of broad-spectrum antibiotics, such as cephalosporins, aminoglycosides and fluoroquinolones over the last 20 years has given rise to significant rates of antibiotic resistance among a broad range of bacterial pathogens [1]. Alarmingly, many of these pathogens have developed resistance to multiple classes of antibiotics. Particular examples are found among the Enterobacteriaceae: Pseudomonas aeruginosa, Acinetobacter baumanni and Staphylococcus spp. specifically MRSA [2,3]. Treatment of these pathogens has become so difficult that physicians are calling for new antibacterial agents with novel modes of action, thereby avoiding existing resistance mechanisms. Ideally, such agents would incorporate other features such as good safety profiles and flexibility in dosage forms and regimens. Recently, there has been growing pressure for effective and widespread implementation of antibiotic stewardship programs to slow or limit the emergence of further bacterial resistance. Experts have advocated the development of narrow-spectrum agents to target specific bacterial species in an effort to reduce off-target selection pressures on the human microbiome [4]. These agents would be more targeted than even vancomycin or linezolid, the use of which led to the development of vancomycinand/or linezolid-resistant enterococci as well as reduced susceptibility or resistance in MRSA. This targeted approach will likely have the additional benefit of causing less disturbance of the commensal flora, resulting in a decrease in such conditions as antibiotic-induced colitis, including Clostridium difficile enterocolitis or candidiasis. Unfortunately, many pharmaceutical companies have withdrawn from antibacterial drug development. Reasons include high-development costs relative to the low sales potential of drugs that are typically used in only short-term treatment regimens, reduced product life due to rapid resistance emergence, and the low probability of identifying a new chemical target that is not compromised by existing resistance mechanisms. The concept of narrow-spectrum agents seems even less appealing due to reduced market potential relative to broad-spectrum agents, despite the potential for a longer window of utility due to reduced emergence of resistance. Genomics-based discovery programs in the early 2000s identified the bacterial fatty-acid (FASII) biosynthetic pathway and the component Fab enzymes (FabA to FabX) as relatively unexploited bacterial targets for antimicrobial agents [5–9]. The Fab family of enzymes are found in all bacteria, with each enzyme catalyzing a step “The clinical role of FabI inhibitors will become clearer over time. They definitely represent a novel and important antibacterial platform that has the potential to address current bacterial resistance problems.”