Please use this identifier to cite or link to this item: http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/7615
Title: A mechanism of salt bridge–mediated resistance to FtsZ inhibitor PC190723 revealed by a cell-based screen
Authors: Sharma, Ajay Kumar
Poddar, Sakshi Mahesh
CHAKRABORTY, JOYEETA
Nayak, Bhagyashri Soumya
Kalathil, Srilakshmi
Mitra, Nivedita
PANANGHAT, GAYATHRI
Srinivasan, Ramanujam
Dept. of Biology
Keywords: Biology
2023-FEB-WEEK2
TOC-FEB-2023
2023
Issue Date: Mar-2023
Publisher: American Society for Cell Biology
Citation: Molecular Biology of the Cell, 34(3).
Abstract: Bacterial cell division proteins, especially the tubulin homolog FtsZ, have emerged as strong targets for developing new antibiotics. Here, we have utilized the fission yeast heterologous expression system to develop a cell-based assay to screen for small molecules that directly and specifically target the bacterial cell division protein FtsZ. The strategy also allows for simultaneous assessment of the toxicity of the drugs to eukaryotic yeast cells. As a proof-of-concept of the utility of this assay, we demonstrate the effect of the inhibitors sanguinarine, berberine and PC190723 on FtsZ. Though sanguinarine and berberine affect FtsZ polymerization, they exert a toxic effect on the cells. Further, using this assay system, we show that PC190723 affects Helicobacter pylori FtsZ function and gain new insights into the molecular determinants of resistance to PC190723. Based on sequence and structural analysis and site-specific mutations, we demonstrate that the presence of salt-bridge interactions between the central H7 helix and beta-strands S9 and S10 mediate resistance to PC190723 in FtsZ. The single-step in vivo cell-based assay using fission yeast enabled us to dissect the contribution of sequence-specific features of FtsZ and cell permeability effects associated with bacterial cell envelopes. Thus, our assay serves as a potent tool to rapidly identify novel compounds targeting polymeric bacterial cytoskeletal proteins like FtsZ to understand how they alter polymerization dynamics and address resistance determinants in targets.
URI: https://doi.org/10.1091/mbc.E22-12-0538
http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/7615
ISSN: 1939-4586
Appears in Collections:JOURNAL ARTICLES

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