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© Giulia Manina, Institut Pasteur
Mycobacterium tuberculosis dual fluorescent reporter of metabolic activity. Green (active bacilli) and red fluorescence (quiescent bacilli) are merged, 100X magnification.
Publication : Frontiers in microbiology

Chemical, Metabolic, and Cellular Characterization of a FtsZ Inhibitor Effective Against Burkholderia cenocepacia.

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Frontiers in microbiology - 01 Jan 2020

Chiarelli LR, Scoffone VC, Trespidi G, Barbieri G, Riabova O, Monakhova N, Porta A, Manina G, Riccardi G, Makarov V, Buroni S,

Link to Pubmed [PMID] – 32318042

Link to DOI – 10.3389/fmicb.2020.00562

Front Microbiol 2020 ; 11(): 562

There is an urgent need for new antimicrobials to treat the opportunistic Gram-negative Burkholderia cenocepacia, which represents a problematic challenge for cystic fibrosis patients. Recently, a benzothiadiazole derivative, C109, was shown to be effective against the infections caused by B. cenocepacia and other Gram-negative and-positive bacteria. C109 has a promising cellular target, the cell division protein FtsZ, and a recently developed PEGylated formulation make it an attractive molecule to counteract Burkholderia infections. However, the ability of efflux pumps to extrude it out of the cell represents a limitation for its use. Here, more than 50 derivatives of C109 were synthesized and tested against Gram-negative species and the Gram-positive Staphylococcus aureus. In addition, their activity was evaluated on the purified FtsZ protein. The chemical, metabolic and cellular stability of C109 has been assayed using different biological systems, including quantitative single-cell imaging. However, no further improvement on C109 was achieved, and the role of efflux in resistance was further confirmed. Also, a novel nitroreductase that can inactivate the compound was characterized, but it does not appear to play a role in natural resistance. All these data allowed a deep characterization of the compound, which will contribute to a further improvement of its properties.

https://pubmed.ncbi.nlm.nih.gov/32318042