title: Selective killing of nonreplicating mycobacteria.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ruslana
authors.initials: R
authors.lastname: Bryk
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gold
authors.forename: Aditya
authors.initials: A
authors.lastname: Venugopal
authors.forename: Jasbir
authors.initials: J
authors.lastname: Singh
authors.forename: Raghu
authors.initials: R
authors.lastname: Samy
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Pupek
authors.forename: Hua
authors.initials: H
authors.lastname: Cao
authors.forename: Carmen
authors.initials: C
authors.lastname: Popescu
authors.forename: Mark
authors.initials: M
authors.lastname: Gurney
authors.forename: Srinivas
authors.initials: S
authors.lastname: Hotha
authors.forename: Joseph
authors.initials: J
authors.lastname: Cherian
authors.forename: Kyu
authors.initials: K
authors.lastname: Rhee
authors.forename: Lan
authors.initials: L
authors.lastname: Ly
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Converse
authors.forename: Sabine
authors.initials: S
authors.lastname: Ehrt
authors.forename: Omar
authors.initials: O
authors.lastname: Vandal
authors.forename: Xiuju
authors.initials: X
authors.lastname: Jiang
authors.forename: Jean
authors.initials: J
authors.lastname: Schneider
authors.forename: Gang
authors.initials: G
authors.lastname: Lin
authors.forename: Carl
authors.initials: C
authors.lastname: Nathan
mesh_terms: 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
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D037521:Virulence Factors; D009569:Nitric Oxide; D012236:Rhodanine; D000217:Acyltransferases; C033588:dihydrolipoamide acyltransferase