Selective killing of nonreplicating mycobacteria.
Antibiotics are typically more effective against replicating rather than nonreplicating bacteria. However, a major need in global health is to eradicate persistent or nonreplicating subpopulations of bacteria such as Mycobacterium tuberculosis (Mtb). Hence, identifying chemical inhibitors that selectively kill bacteria that are not replicating is of practical importance. To address this, we screened for inhibitors of dihydrolipoamide acyltransferase (DlaT), an enzyme required by Mtb to cause tuberculosis in guinea pigs and used by the bacterium to resist nitric oxide-derived reactive nitrogen intermediates, a stress encountered in the host. Chemical screening for inhibitors of Mtb DlaT identified select rhodanines as compounds that almost exclusively kill nonreplicating mycobacteria in synergy with products of host immunity, such as nitric oxide and hypoxia, and are effective on bacteria within macrophages, a cellular reservoir for latent Mtb. Compounds that kill nonreplicating pathogens in cooperation with host immunity could complement the conventional chemotherapy of infectious disease.
Bryk
Ruslana
R
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
Gold
Benjamin
B
Venugopal
Aditya
A
Singh
Jasbir
J
Samy
Raghu
R
Pupek
Krzysztof
K
Cao
Hua
H
Popescu
Carmen
C
Gurney
Mark
M
Hotha
Srinivas
S
Cherian
Joseph
J
Rhee
Kyu
K
Ly
Lan
L
Converse
Paul J
PJ
Ehrt
Sabine
S
Vandal
Omar
O
Jiang
Xiuju
X
Schneider
Jean
J
Lin
Gang
G
Nathan
Carl
C
D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017353:Gene Deletion; D005816:Genetic Complementation Test; D006168:Guinea Pigs; D000860:Hypoxia / Q000276:immunology; D008168:Lung / Q000382:microbiology; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D050296:Microbial Viability / Q000187:drug effects*; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D009569:Nitric Oxide / Q000276:immunology; D012236:Rhodanine / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology; D014774:Virulence; D037521:Virulence Factors / Q000037:antagonists & inhibitors / Q000235:genetics
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D037521:Virulence Factors; D009569:Nitric Oxide; D012236:Rhodanine; D000217:Acyltransferases; C033588:dihydrolipoamide acyltransferase