SQ109 and PNU-100480 interact to kill Mycobacterium tuberculosis in vitro

• Published in: Journal of antimicrobial chemotherapy Vol. 67; no. 5; pp. 1163 - 1166
• Main Authors: REDDY, Venkata M, DUBUISSON, Tia, EINCK, Leo, WALLIS, Robert S, JAKUBIEC, Wesley, LADUKTO, Lynn, CAMPBELL, Sheldon, NACY, Carol A
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.05.2012; Oxford Publishing Limited (England)
• Subjects: Adamantane - analogs & derivatives; Adamantane - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antitubercular Agents - pharmacology; Bacteria; Bactericidal activity; Biological and medical sciences; Blood culture; Cell Line; Chemical compounds; Data processing; Drug Interactions; Drug resistance; Drugs; Ethylenediamines - pharmacology; Macrophages; Macrophages - microbiology; Medical sciences; Metabolites; Mice; Microbial Viability - drug effects; Minimum inhibitory concentration; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; oxazolidinones; Oxazolidinones - pharmacology; Pharmacology; Pharmacology. Drug treatments; Titration; Tuberculosis; rate of killing; In vitro; Biological activity; Whole blood; intracellular activity; Mycobacterium tuberculosis; whole blood bactericidal activity; Mycobacteriales; Mycobacteriaceae; Bacteria; Actinomycetes; Intracellular; Antibacterial agent
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkr589

To investigate in vitro interaction between two compounds, SQ109 and PNU-100480, currently in development for the treatment of Mycobacterium tuberculosis (MTB). The two-drug interactions between SQ109 and PNU-100480 and its major metabolite PNU-101603 were assessed by chequerboard titration, and the rate of killing and intracellular activity were determined in both J774A.1 mouse macrophages and whole blood culture. In chequerboard titration, interactions between SQ109 and either oxazolidinone were additive. In time-kill studies, SQ109 killed MTB faster than PNU compounds, and its rate of killing was further enhanced by both oxazolidinones. The order of efficacy of single compounds against intracellular MTB was SQ109 > PNU-100480 > PNU-101603. At sub-MIC, combinations of SQ109 + PNU compounds showed improved intracellular activity over individual drugs; at ≥MIC, the order of efficacy was SQ109 > SQ109 + PNU-100480 > SQ109 + PNU-101603. In whole blood culture, the combined bactericidal activities of SQ109 and PNU-100480 and its major metabolite against intracellular M. tuberculosis did not differ significantly from the sum of the compounds tested individually. SQ109 and PNU combinations were additive and improved the rate of MTB killing over individual drugs. These data suggest that the drugs may work together cooperatively to eliminate MTB in vivo.