Mycolic Acid Cyclopropanation is Essential for Viability, Drug Resistance, and Cell Wall Integrity of Mycobacterium tuberculosis

Journal Article · Tue Dec 01 04:00:00 EST 2009 · Chem. Biol.

DOI:https://doi.org/10.1016/j.chembiol.2009.04.001· OSTI ID:1005739

Barkan, Daniel; Liu, Zhen; Sacchettini, James C; Glickman, Michael S

Mycobacterium tuberculosis infection remains a major global health problem complicated by escalating rates of antibiotic resistance. Despite the established role of mycolic acid cyclopropane modification in pathogenesis, the feasibility of targeting this enzyme family for antibiotic development is unknown. We show through genetics and chemical biology that mycolic acid methyltransferases are essential for M. tuberculosis viability, cell wall structure, and intrinsic resistance to antibiotics. The tool compound dioctylamine, which we show acts as a substrate mimic, directly inhibits the function of multiple mycolic acid methyltransferases, resulting in loss of cyclopropanation, cell death, loss of acid fastness, and synergistic killing with isoniazid and ciprofloxacin. These results demonstrate that mycolic acid methyltransferases are a promising antibiotic target and that a family of virulence factors can be chemically inhibited with effects not anticipated from studies of each individual enzyme.

• Research Organization: Argonne National Laboratory (ANL)
• Sponsoring Organization: USDOE
• OSTI ID: 1005739
• Journal Information: Chem. Biol., Journal Name: Chem. Biol. Journal Issue: (5) ; 05, 2009 Vol. 16; ISSN 1074-5521
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
ANTIBIOTICS
BIOLOGY
CELL WALL
ENZYMES
GENETICS
ISONIAZID
MODIFICATIONS
MYCOBACTERIUM TUBERCULOSIS
PATHOGENESIS
SUBSTRATES
TARGETS
TUBERCULOSIS
VIABILITY
VIRULENCE