A mechanism of salt bridge–mediated resistance to FtsZ inhibitor PC190723 revealed by a cell-based screen
Ajay Sharma, Sakshi Mahesh Poddar, Joyeeta Chakraborty, Bhagyashri Soumya Nayak, Srilakshmi Kalathil, Nivedita Mitra, Pananghat Gayathri, R. Srinivasan
Abstract
FtsZ function and gain new insights into the molecular determinants of resistance to PC190723. On the basis of sequence and structural analysis and site-specific mutations, we demonstrate that the presence of salt bridge interactions between the central H7 helix and β-strands S9 and S10 mediates 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.