Development of small-molecule inhibitors of fatty acyl-AMP and fatty acyl-CoA ligases in Mycobacterium tuberculosis

Marzena Baran, Kimberly D. Grimes, Paul A. Sibbald, Peng Fu, Helena I.M. Boshoff, Daniel J. Wilson, Courtney C. Aldrich

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Lipid metabolism in Mycobacterium tuberculosis (Mtb) relies on 34 fatty acid adenylating enzymes (FadDs) that can be grouped into two classes: fatty acyl-CoA ligases (FACLs) involved in lipid and cholesterol catabolism and long chain fatty acyl-AMP ligases (FAALs) involved in biosynthesis of the numerous essential and virulence-conferring lipids found in Mtb. The precise biochemical roles of many FACLs remain poorly characterized while the functionally non-redundant FAALs are much better understood. Here we describe the systematic investigation of 5′-O-[N-(alkanoyl)sulfamoyl]adenosine (alkanoyl adenosine monosulfamate, alkanoyl-AMS) analogs as potential multitarget FadD inhibitors for their antitubercular activity and biochemical selectivity towards representative FAAL and FACL enzymes. We identified several potent compounds including 12-azidododecanoyl-AMS 28, 11-phenoxyundecanoyl-AMS 32, and nonyloxyacetyl-AMS 36 with minimum inhibitory concentrations (MICs) against M. tuberculosis ranging from 0.098 to 3.13 μM. Compound 32 was notable for its impressive biochemical selectivity against FAAL28 (apparent Ki = 0.7 μM) versus FACL19 (Ki > 100 μM), and uniform activity against a panel of multidrug and extensively drug-resistant TB strains with MICs ranging from 3.13 to 12.5 μM in minimal (GAST) and rich (7H9) media. The SAR analysis provided valuable insights for further optimization of 32 and also identified limitations to overcome.

Original languageEnglish (US)
Article number112408
JournalEuropean Journal of Medicinal Chemistry
Volume201
DOIs
StatePublished - Sep 1 2020

Bibliographical note

Funding Information:
This research was supported by a grant from the Great Lakes Regional Center of Excellence ( GLRCE , 2U54AI057153 ), the National Institutes of Health ( AI136445 ) and funded (in part) by the Intramural Research Program of the NIAID, NIH .

Keywords

  • Acyl-AMS analogs
  • FAAL28
  • FACL19
  • Fatty acyl-AMP ligases
  • Fatty acyl-CoA ligases
  • Mycobacterium tuberculosis

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