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

被引：41

作者：

Reddy, Venkata M. ^{[1
]}

Dubuisson, Tia ^{[1
]}

Einck, Leo ^{[1
]}

Wallis, Robert S. ^{[2
]}

Jakubiec, Wesley ^{[3
]}

Ladukto, Lynn ^{[3
]}

Campbell, Sheldon ^{[3
]}

Nacy, Carol A. ^{[1
]}

机构：

[1] Sequella Inc, Rockville, MD 20850 USA

[2] Pfizer Inc, Groton, CT 06340 USA

[3] VA Connecticut Healthcare Syst, West Haven, CT USA

来源：

JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY | 2012年 / 67卷 / 05期

关键词：

rate of killing; intracellular activity; whole blood bactericidal activity; PULMONARY TUBERCULOSIS; BACTERICIDAL ACTIVITY;

D O I：

10.1093/jac/dkr589

中图分类号：

R51 [传染病];

学科分类号：

100401 ;

摘要：

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 timekill 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 SQ109PNU-100480PNU-101603. At sub-MIC, combinations of SQ109PNU compounds showed improved intracellular activity over individual drugs; at epsilon MIC, the order of efficacy was SQ109SQ109PNU-100480SQ109PNU-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.

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页码：1163 / 1166

页数：4

相关论文

共 10 条

[1] Susceptibility of Clinical Mycobacterium tuberculosis Isolates to a Potentially Less Toxic Derivate of Linezolid, PNU-100480 [J].

Alffenaar, J. W. C. ;

van der Laan, T. ;

Simons, S. ;

van der Werf, T. S. ;

van de Kasteele, P. J. ;

de Neeling, H. ;

van Soolingen, D. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2011, 55 (03) :1287-1289

[2] Chemical modification of capuramycins to enhance antibacterial activity [J].

Bogatcheva, Elena ;

Dubuisson, Tia ;

Protopopova, Marina ;

Einck, Leo ;

Nacy, Carol A. ;

Reddy, Venkata M. .

JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 2011, 66 (03) :578-587

[3] Early and Extended Early Bactericidal Activity of Linezolid in Pulmonary Tuberculosis [J].

Dietze, Reynaldo ;

Hadad, David Jamil ;

McGee, Bryan ;

Molino, Lucilia Pereira Dutra ;

Maciel, Ethel Leonor Noia ;

Peloquin, Charles A. ;

Johnson, Denise F. ;

Debanne, Sara M. ;

Eisenach, Kathleen ;

Boom, W. Henry ;

Palaci, Moises ;

Johnson, John L. .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2008, 178 (11) :1180-1185

[4] MECHANISM OF ACTION OF DUP-721 - INHIBITION OF AN EARLY EVENT DURING INITIATION OF PROTEIN-SYNTHESIS [J].

EUSTICE, DC ;

FELDMAN, PA ;

ZAJAC, I ;

SLEE, AM .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1988, 32 (08) :1218-1222

[5] Drug therapy of experimental tuberculosis (TB): Improved outcome by combining SQ109, a new diamine antibiotic, with existing TB drugs [J].

Nikonenko, Boris V. ;

Protopopova, Marina ;

Sarnala, Rowena ;

Einck, Leo ;

Nacy, Carol A. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2007, 51 (04) :1563-1565

[6] Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines [J].

Protopopova, M ;

Hanrahan, C ;

Nikonenko, B ;

Samala, R ;

Chen, P ;

Gearhart, J ;

Einck, L ;

Nacy, CA .

JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 2005, 56 (05) :968-974

[7] In Vitro Interactions between New Antitubercular Drug Candidates SQ109 and TMC207 [J].

Reddy, Venkata M. ;

Einck, Leo ;

Andries, K. ;

Nacy, Carol A. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2010, 54 (07) :2840-2846

[8] Biomarker-Assisted Dose Selection for Safety and Efficacy in Early Development of PNU-100480 for Tuberculosis [J].

Wallis, Robert S. ;

Jakubiec, Wesley ;

Kumar, Vikas ;

Bedarida, Gabriella ;

Silvia, Annette ;

Paige, Darcy ;

Zhu, Tong ;

Mitton-Fry, Mark ;

Ladutko, Lynn ;

Campbell, Sheldon ;

Miller, Paul F. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2011, 55 (02) :567-574

[9] Whole blood bactericidal activity during treatment of pulmonary tuberculosis [J].

Wallis, RS ;

Vinhas, SA ;

Johnson, JL ;

Ribeiro, FC ;

Palaci, M ;

Peres, RL ;

Sá, RT ;

Dietze, R ;

Chiunda, A ;

Eisenach, K ;

Ellner, JJ .

JOURNAL OF INFECTIOUS DISEASES, 2003, 187 (02) :270-278

[10] Promising Antituberculosis Activity of the Oxazolidinone PNU-100480 Relative to That of Linezolid in a Murine Model [J].

Williams, K. N. ;

Stover, C. K. ;

Zhu, T. ;

Tasneen, R. ;

Tyagi, S. ;

Grosset, J. H. ;

Nuermberger, E. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2009, 53 (04) :1314-1319