title: Monocarbonyl analogs of curcumin inhibit growth of antibiotic sensitive and resistant strains of Mycobacterium tuberculosis.
abstract: Tuberculosis (TB) is a major public health concern worldwide with over 2 billion people currently infected. The rise of strains of Mycobacterium tuberculosis (Mtb) that are resistant to some or all first and second line antibiotics, including multidrug-resistant (MDR), extensively drug resistant (XDR) and totally drug resistant (TDR) strains, is of particular concern and new anti-TB drugs are urgently needed. Curcumin, a natural product used in traditional medicine in India, exhibits anti-microbial activity that includes Mtb, however it is relatively unstable and suffers from poor bioavailability. To improve activity and bioavailability, mono-carbonyl analogs of curcumin were synthesized and screened for their capacity to inhibit the growth of Mtb and the related Mycobacterium marinum (Mm). Using disk diffusion and liquid culture assays, we found several analogs that inhibit in vitro growth of Mm and Mtb, including rifampicin-resistant strains. Structure activity analysis of the analogs indicated that Michael acceptor properties are critical for inhibitory activity. However, no synergistic effects were evident between the monocarbonyl analogs and rifampicin on inhibiting growth. Together, these data provide a structural basis for the development of analogs of curcumin with pronounced anti-mycobacterial activity and provide a roadmap to develop additional structural analogs that exhibit more favorable interactions with other anti-TB drugs.
authors.affiliation: Department of Chemistry, Emory University, Atlanta GA 30322, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Baldwin
authors.affiliation: Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta GA 30333, USA; Microbiology and Molecular Genetics Graduate Program, Emory University School of Medicine, Atlanta GA 30322, USA.
authors.forename: Analise Z
authors.initials: AZ
authors.lastname: Reeves
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta GA 30322, USA.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Powell
authors.affiliation: Microbiology and Molecular Genetics Graduate Program, Emory University School of Medicine, Atlanta GA 30322, USA.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Napier
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta GA 30322, USA.
authors.forename: Alyson I
authors.initials: AI
authors.lastname: Swimm
authors.affiliation: Department of Chemistry, Emory University, Atlanta GA 30322, USA.
authors.forename: Aiming
authors.initials: A
authors.lastname: Sun
authors.affiliation: Department of Chemistry, Emory University, Atlanta GA 30322, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Giesler
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta GA 30322, USA.
authors.forename: Bettina
authors.initials: B
authors.lastname: Bommarius
authors.affiliation: Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta GA 30333, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Shinnick
authors.affiliation: Department of Chemistry, Emory University, Atlanta GA 30322, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.affiliation: Department of Chemistry, Emory University, Atlanta GA 30322, USA.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta GA 30322, USA. Electronic address: dkalman@emory.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kalman
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D003474:Curcumin
keywords: Curcumin; Curcumin analogs; Mycobacteria; Tuberculosis