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A synthetic diterpene analogue inhibits mycobacterial persistence and biofilm formation by targeting (p)ppGpp synthetases

journal contribution
posted on 27.01.2021, 10:04 by Alexaner G Tkachenko, Natalya Kashevarova, Roman Sidorov, Larisa Nesterova, Anna Akhova, Ivan Tsyganov, Vladimir Vaganov, Sergei Shipilovskikh, Aleksandr Rubtsov, Andrei Malkov
Bacterial persistence coupled with biofilm formation is directly associated with failure of antibiotic treatment of TB. We have now identified 4-(4,7-DiMethyl-1,2,3,4-tetrahydroNaphthalene-1-yl)Pentanoic acid (DMNP), a synthetic diterpene analogue, as a lead compound that was capable of suppressing persistence and eradicating biofilms in Mycobacterium smegmatis. By using two reciprocal experimental approaches – DrelMsm and DrelZ gene knockout mutations versus relMsm and relZ overexpression technique – we showed that both RelMsm and RelZ (p)ppGpp synthetases are plausible candidates for serving as targets for DMNP. In vitro, DMNP inhibited (p)ppGpp synthesizing activity of purified RelMsm in a concentration-dependent manner. These findings, supplemented by molecular docking simulation, suggest that DMNP targets the structural sites shared by RelMsm, RelZ and presumably by a few others as yet unidentified (p)ppGpp producers, thereby inhibiting persister cell formation and eradicating biofilms. Therefore, DMNP may serve as a promising lead for development of antimycobacterial drugs.

Funding

Russian Science Foundation Grant No. 18-73-10156

History

School

  • Science

Department

  • Chemistry

Published in

Cell Chemical Biology

Publisher

Elsevier

Version

AM (Accepted Manuscript)

Publisher statement

This paper was accepted for publication in the journal Cell Chemical Biology and the definitive published version is available at https://doi.org/10.1016/j.chembiol.2021.01.018

Acceptance date

25/01/2021

Publication date

2021-02-22

ISSN

2451-9456

eISSN

2451-9448

Language

en

Depositor

Prof Andrei Malkov. Deposit date: 25 January 2021

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