Mining Fatty Acid Biosynthesis for New Antimicrobials

Antibiotic resistance is a serious public health concern, and new drugs are needed to ensure effective treatment of many bacterial infections. Bacterial type II fatty acid synthesis (FASII) is a vital aspect of bacterial physiology, not only for the formation of membranes but also to produce intermediates used in vitamin production. Nature has evolved a repertoire of antibiotics inhibiting different aspects of FASII, validating these enzymes as potential targets for new antibiotic discovery and development. However, significant obstacles have been encountered in the development of FASII antibiotics, and few FASII drugs have advanced beyond the discovery stage. Most bacteria are capable of assimilating exogenous fatty acids. In some cases they can dispense with FASII if fatty acids are present in the environment, making the prospects for identifying broad-spectrum drugs against FASII targets unlikely. Single-target, pathogen-specific FASII drugs appear the best option, but a major drawback to this approach is the rapid acquisition of resistance via target missense mutations. This complication can be mitigated during drug development by optimizing the compound design to reduce the potential impact of on-target missense mutations at an early stage in antibiotic discovery. The lessons learned from the difficulties in FASII drug discovery that have come to light over the last decade suggest that a refocused approach to designing FASII inhibitors has the potential to add to our arsenal of weapons to combat resistance to existing antibiotics.