Abstract
The recent increase in antibiotic resistance in pathogenic bacteria calls for new approaches to drug-target selection and drug development. Targeting the mechanisms of action of proteins involved in bacterial cell division bypasses problems associated with increasingly ineffective variants of older antibiotics; to this end, the essential bacterial cytoskeletal protein FtsZ is a promising target. Recent work on its allosteric inhibitor, PC190723, revealed in vitro activity on Staphylococcus aureus FtsZ and in vivo antimicrobial activities. However, the mechanism of drug action and its effect on FtsZ in other bacterial species are unclear. Here, we examine the structural environment of the PC190723 binding pocket using PocketFEATURE, a statistical method that scores the similarity between pairs of small-molecule binding sites based on 3D structure information about the local microenvironment, and molecular dynamics (MD) simulations. We observed that species and nucleotide-binding state have significant impacts on the structural properties of the binding site, with substantially disparate microenvironments for bacterial species not from the Staphylococcus genus. Based on PocketFEATURE analysis of MD simulations of S. aureus FtsZ bound to GTP or with mutations that are known to confer PC190723 resistance, we predict that PC190723 strongly prefers to bind Staphylococcus FtsZ in the nucleotide-bound state. Furthermore, MD simulations of an FtsZ dimer indicated that polymerization may enhance PC190723 binding. Taken together, our results demonstrate that a drug-binding pocket can vary significantly across species, genetic perturbations, and in different polymerization states, yielding important information for the further development of FtsZ inhibitors.
Highlights
Rises in bacterial antibiotic resistance have motivated the development of new classes of drugs with alternative mechanisms of action [1]
The rise of antibiotic resistance in microbes that cause dangerous diseases necessitates the development of new drugs with novel mechanisms of antimicrobial activity
All-atom molecular dynamics (MD) simulations predicted that force generation may result from a dramatic bending in GDP-bound filaments induced by nucleotide hydrolysis [10]; this conformational change was later confirmed by X-ray crystallography [6]
Summary
Rises in bacterial antibiotic resistance have motivated the development of new classes of drugs with alternative mechanisms of action [1]. Single point mutations conferring resistance to PC190723 in S. aureus were identified within ftsZ, suggesting that PC190723 binds to S. aureus FtsZ (SaFtsZ) This observation was later confirmed via the co-crystallization of an SaFtsZ-PC190723 complex in two independent studies [17,18]; currently PC190723 is the only FtsZ-targeting drug with evidence of direct binding. In both co-crystals, PC190723 binds a pocket beneath the H7 loop close to the C-terminus of FtsZ, and many of the FtsZ residues with identified resistance mutations (for example, G193, G196, and N263) lie within 6 Å of the PC190723 molecule in these structures (Fig. 1). The PC190723-binding pocket is quite far from FtsZ’s GTP-binding site, it is situated near the T7 loop, which is thought to contact the GTP-binding pocket of an adjacent FtsZ subunit after polymerization, forming the catalytic active site for GTP hydrolysis [19]
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