Mining Fatty Acid Biosynthesis for New Antimicrobials

Christopher D. Radka, Charles O. Rock

Research output: Contribution to journalReview articlepeer-review

7 Scopus citations


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.

Original languageEnglish
Pages (from-to)281-304
Number of pages24
JournalAnnual Review of Microbiology
StatePublished - Sep 8 2022

Bibliographical note

Funding Information:
This laboratory research was supported by the National Institutes of Health through grants AI166116 and GM034496, Cancer Center Support Grant CA21765, and the American Lebanese Syrian Associated Charities

Publisher Copyright:
Copyright © 2022 by Annual Reviews. All rights reserved.


  • antibiotic resistance
  • antibiotics
  • natural products
  • pathogenspecific antibiotics
  • type II fatty acid synthesis

ASJC Scopus subject areas

  • Microbiology


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