000216825 001__ 216825
000216825 005__ 20181203024159.0
000216825 0247_ $$2doi$$a10.1371/journal.pntd.0004022
000216825 022__ $$a1935-2735
000216825 02470 $$2ISI$$a000364459600010
000216825 037__ $$aARTICLE
000216825 245__ $$aIn Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis
000216825 260__ $$aSan Francisco$$bPublic Library of Science$$c2015
000216825 269__ $$a2015
000216825 300__ $$a11
000216825 336__ $$aJournal Articles
000216825 520__ $$aBackground Mycetoma is a neglected, chronic, and deforming infectious disease caused by fungi and actinomycetes. In Mexico, N. brasiliensis is the predominant etiologic agent. Therapeutic alternatives are necessary because the current drug regimens have several disadvantages. Benzothiazinones (BTZ) are a new class of candidate drugs that inhibit decaprenylphosphoribose- epimerase (DprE1), an essential enzyme involved in the cell wall biosynthesis of Corynebacterineae. Methodology/Principal findings In this study, the in vitro activity of the next generation BTZ, PBTZ169, was tested against thirty Nocardia brasiliensis isolates. The MIC50 and MIC90 values for PBTZ169 were 0.0075 and 0.03 mu g/mL, respectively. Because Nocardia is a potential intracellular bacterium, a THP-1 macrophage monolayer was infected with N. brasiliensis HUJEG-1 and then treated with PBTZ169, resulting in a decrease in the number of colony-forming units (CFUs) at a concentration of 0.25X the in vitro value. The in vivo activity was evaluated after infecting female BALB/c mice in the right hind food-pad. After 6 weeks, treatment was initiated with PBTZ169 and its activity was compared with the first generation compound, BTZ043. Both BTZ compounds were administered at 100 mg/kg twice daily by gavage, and sulfamethoxazole/trimethoprim (SXT), at 100 mg/kg sulfamethoxazole, was used as a positive control. After 22 weeks of therapy, only PBTZ169 and SXT displayed statistically significant activity. Conclusion These results indicate that DprE1 inhibitors may be useful for treating infections of Nocardia and may therefore be active against other actinomycetoma agents. We must test combinations of these compounds with other antimicrobial agents, such as linezolid, tedizolid or SXT, that have good to excellent in vivo activity, as well as new DprE1 inhibitors that can achieve higher plasma levels.
000216825 700__ $$aAlejandra Gonzalez-Martinez, Norma$$uHosp Univ Dr Jose Eleuterio Gonzalez, Serv Dermatol, Lab Interdisciplinario Invest Dermatol, Monterrey, Nuevo Leon, Mexico
000216825 700__ $$aGerardo Lozano-Garza, Hector$$uIMSS, Ctr Invest Biomed Noreste, Monterrey, Nuevo Leon, Mexico
000216825 700__ $$aCastro-Garza, Jorge$$uIMSS, Ctr Invest Biomed Noreste, Monterrey, Nuevo Leon, Mexico
000216825 700__ $$aDe Osio-Cortez, Alexandra$$uHosp Univ Dr Jose Eleuterio Gonzalez, Serv Dermatol, Lab Interdisciplinario Invest Dermatol, Monterrey, Nuevo Leon, Mexico
000216825 700__ $$aVargas-Villarreal, Javier$$uIMSS, Ctr Invest Biomed Noreste, Monterrey, Nuevo Leon, Mexico
000216825 700__ $$aCavazos-Rocha, Norma$$uUANL, Dept Quim Analit, Fac Med, Monterrey, Nuevo Leon, Mexico
000216825 700__ $$aOcampo-Candiani, Jorge$$uHosp Univ Dr Jose Eleuterio Gonzalez, Serv Dermatol, Lab Interdisciplinario Invest Dermatol, Monterrey, Nuevo Leon, Mexico
000216825 700__ $$aMakarov, Vadim$$uRussian Acad Sci, AN Bakh Biochem Inst, Moscow, Russia
000216825 700__ $$0243892$$aCole, Stewart T.$$g177247
000216825 700__ $$aVera-Cabrera, Lucio$$uHosp Univ Dr Jose Eleuterio Gonzalez, Serv Dermatol, Lab Interdisciplinario Invest Dermatol, Monterrey, Nuevo Leon, Mexico
000216825 773__ $$j9$$k10$$qe0004022$$tPLoS Neglected Tropical Diseases
000216825 909C0 $$0252302$$pUPCOL$$xU11742
000216825 909CO $$ooai:infoscience.tind.io:216825$$pSV$$particle
000216825 917Z8 $$x217823
000216825 937__ $$aEPFL-ARTICLE-216825
000216825 973__ $$aEPFL$$rREVIEWED$$sPUBLISHED
000216825 980__ $$aARTICLE