Diphenylether-Modified 1,2-Diamines with Improved Drug Properties for Development against Mycobacterium tuberculosis.
New treatments for tuberculosis infection are critical to combat the emergence of multidrug- and extensively drug-resistant Mycobacterium tuberculosis (Mtb). We report the characterization of a diphenylether-modified adamantyl 1,2-diamine that we refer to as TBL-140, which has a minimal inhibitory concentration (MIC99) of 1.2 μg/mL. TBL-140 is effective against drug-resistant Mtb and nonreplicating bacteria. In addition, TBL-140 eliminates expansion of Mtb in cell culture infection assays at its MIC. To define the mechanism of action of this compound, we performed a spontaneous mutant screen and biochemical assays. We determined that TBL-140 treatment affects the proton motive force (PMF) by perturbing the transmembrane potential (ΔΨ), consistent with a target in the electron transport chain (ETC). As a result, treated bacteria have reduced intracellular ATP levels. We show that TBL-140 exhibits greater metabolic stability than SQ109, a structurally similar compound in clinical trials for treatment of MDR-TB infections. Combined, these results suggest that TBL-140 should be investigated further to assess its potential as an improved therapeutic lead against Mtb.
Department of Molecular Microbiology & Immunology, Oregon Health & Science University , 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, United States.
Marie H
MH
Foss
Portland VA Medical Center , 3710 S.W. U.S. Veterans Hospital Road, Portland, Oregon 97239, United States.
Sovitj
S
Pou
Department of Molecular Microbiology & Immunology, Oregon Health & Science University , 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, United States.
Patrick M
PM
Davidson
Department of Molecular Microbiology & Immunology, Oregon Health & Science University , 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, United States.
Jennifer L
JL
Dunaj
Portland VA Medical Center , 3710 S.W. U.S. Veterans Hospital Road, Portland, Oregon 97239, United States.
Rolf W
RW
Winter
Portland VA Medical Center , 3710 S.W. U.S. Veterans Hospital Road, Portland, Oregon 97239, United States.
Sovijja
S
Pou
Department of Molecular Microbiology & Immunology, Oregon Health & Science University , 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, United States.
Meredith H
MH
Licon
Department of Molecular Microbiology & Immunology, Oregon Health & Science University , 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, United States.
Julia K
JK
Doh
Portland VA Medical Center , 3710 S.W. U.S. Veterans Hospital Road, Portland, Oregon 97239, United States.
Yuexin
Y
Li
Portland VA Medical Center , 3710 S.W. U.S. Veterans Hospital Road, Portland, Oregon 97239, United States.
Jane X
JX
Kelly
Portland VA Medical Center , 3710 S.W. U.S. Veterans Hospital Road, Portland, Oregon 97239, United States.
Rozalia A
RA
Dodean
Department of Physiology and Pharmacology, Oregon Health & Science University , 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, United States.
Dennis R
DR
Koop
Department of Molecular Microbiology & Immunology, Oregon Health & Science University , 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, United States.|Portland VA Medical Center , 3710 S.W. U.S. Veterans Hospital Road, Portland, Oregon 97239, United States.
Michael K
MK
Riscoe
Department of Molecular Microbiology & Immunology, Oregon Health & Science University , 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, United States.
Georgiana E
GE
Purdy
D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D003959:Diamines / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D010647:Phenyl Ethers / Q000737:chemistry; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology*
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D003959:Diamines; D010647:Phenyl Ethers; C031538:phenyl ether
MmpL3; antibiotic; drug development; proton motive force; tuberculosis