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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

A systems chemical biology study of malate synthase and isocitrate lyase inhibition in Mycobacterium tuberculosis during active and NRP growth

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May, Elebeoba E. [1] ; Leitao, Andrei [2] ; Tropsha, Alexander [3] ; Oprea, Tudor I. [4]
Total Authors: 4
[1] Univ Houston, Dept Biomed Engn, Houston, TX 77204 - USA
[2] Univ Sao Paulo, Inst Chem Sao Carlos, Med Chem Grp NEQUIMED, Sao Carlos, SP - Brazil
[3] Univ N Carolina, Eshelman Sch Pharm, Div Med Chem & Nat Prod, Lab Mol Modeling, Chapel Hill, NC 27599 - USA
[4] Univ New Mexico, Sch Med, Dept Internal Med, Albuquerque, NM 87131 - USA
Total Affiliations: 4
Document type: Journal article
Source: COMPUTATIONAL BIOLOGY AND CHEMISTRY; v. 47, p. 167-180, DEC 2013.
Web of Science Citations: 5

The ability of Mycobacterium tuberculosis (Mtb) to survive in low oxygen environments enables the bacterium to persist in a latent state within host tissues. In vitro studies of Mtb growth have identified changes in isocitrate lyase (ICL) and malate synthase (MS) that enable bacterial persistence under low oxygen and other environmentally limiting conditions. Systems chemical biology (SCB) enables us to evaluate the effects of small molecule inhibitors not only on the reaction catalyzed by malate synthase and isocitrate lyase, but the effect on the complete tricarboxylic acid cycle (TCA) by taking into account complex network relationships within that system. To study the kinetic consequences of inhibition on persistent bacilli, we implement a systems-chemical biology (SCB) platform and perform a chemistry-centric analysis of key metabolic pathways believed to impact Mtb latency. We explore consequences of disrupting the function of malate synthase (MS) and isocitrate lyase (ICL) during aerobic and hypoxic non-replicating persistence (NRP) growth by using the SCB method to identify small molecules that inhibit the function of MS and ICL, and simulating the metabolic consequence of the disruption. Results indicate variations in target and non-target reaction steps, clear differences in the normal and low oxygen models, as well as dosage dependent response. Simulation results from singular and combined enzyme inhibition strategies suggest ICL may be the more effective target for chemotherapeutic treatment against Mtb growing in a microenvironment where oxygen is slowly depleted, which may favor persistence. (C) 2013 Elsevier Ltd. All rights reserved. (AU)

FAPESP's process: 11/07025-3 - In silico studies and cell-based assays to identify new therapeutic approaches to prostate cancer
Grantee:Andrei Leitão
Support Opportunities: Regular Research Grants