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Inhibitors of bacterial tubulin target bacterial membranes in vivo.

ABSTRACT: FtsZ is a homolog of eukaryotic tubulin that is widely conserved among bacteria and coordinates the assembly of the cell division machinery. FtsZ plays a central role in cell replication and is a target of interest for antibiotic development. Several FtsZ inhibitors have been reported. We characterized the mechanism of these compounds in bacteria and found that many of them disrupt the localization of membrane-associated proteins, including FtsZ, by reducing the transmembrane potential or perturbing membrane permeability. We tested whether the reported phenotypes of a broad collection of FtsZ inhibitors disrupt the transmembrane potential in Bacillus subtilis strain 168. Using a combination of flow cytometry and microscopy, we found that zantrin Z1, cinnamaldehyde, totarol, sanguinarine, and viriditoxin decreased the B. subtilis transmembrane potential or perturbed membrane permeability, and influenced the localization of the membrane-associated, division protein MinD. These studies demonstrate that small molecules that disrupt membrane function in bacterial cells produce phenotypes that are similar to the inhibition of proteins associated with membranes in vivo, including bacterial cytoskeleton homologs, such as FtsZ. The results provide a new dimension for consideration in the design and testing of inhibitors of bacterial targets that are membrane-associated and provide additional insight into the structural characteristics of antibiotics that disrupt the membrane.

SUBMITTER: Foss MH

PROVIDER: S-EPMC3607388 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Inhibitors of bacterial tubulin target bacterial membranes <i>in vivo.</i>

Foss Marie H MH Eun Ye-Jin YJ Grove Charles I CI Pauw Daniel A DA Sorto Nohemy A NA Rensvold Jarred W JW Pagliarini David J DJ Shaw Jared T JT Weibel Douglas B DB

MedChemComm 20120718 1

FtsZ is a homolog of eukaryotic tubulin that is widely conserved among bacteria and coordinates the assembly of the cell division machinery. FtsZ plays a central role in cell replication and is a target of interest for antibiotic development. Several FtsZ inhibitors have been reported. We characterized the mechanism of these compounds in bacteria and found that many of them disrupt the localization of membrane-associated proteins, including FtsZ, by reducing the transmembrane potential or pertur ...[more]

PMID: 23539337

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Project description:BACKGROUND: The emergence of drug resistant tuberculosis poses a serious concern globally and researchers are in rigorous search for new drugs to fight against these dreadful bacteria. Recently, the bacterial GlmU protein, involved in peptidoglycan, lipopolysaccharide and techoic acid synthesis, has been identified as an important drug target. A unique C-terminal disordered tail, essential for survival and the absence of gene in host makes GlmU a suitable target for inhibitor design. RESULTS: This study describes the models developed for predicting inhibitory activity (IC50) of chemical compounds against GlmU protein using QSAR and docking techniques. These models were trained on 84 diverse compounds (GlmU inhibitors) taken from PubChem BioAssay (AID 1376). These inhibitors were docked in the active site of the C-terminal domain of GlmU protein (2OI6) using the AutoDock. A QSAR model was developed using docking energies as descriptors and achieved maximum correlation of 0.35/0.12 (r/r2) between actual and predicted pIC50. Secondly, QSAR models were developed using molecular descriptors calculated using various software packages and achieved maximum correlation of 0.77/0.60 (r/r2). Finally, hybrid models were developed using various types of descriptors and achieved high correlation of 0.83/0.70 (r/r2) between predicted and actual pIC50. It was observed that some molecular descriptors used in this study had high correlation with pIC50. We screened chemical libraries using models developed in this study and predicted 40 potential GlmU inhibitors. These inhibitors could be used to develop drugs against Mycobacterium tuberculosis. CONCLUSION: These results demonstrate that docking energies can be used as descriptors for developing QSAR models. The current work suggests that docking energies based descriptors could be used along with commonly used molecular descriptors for predicting inhibitory activity (IC50) of molecules against GlmU. Based on this study an open source platform, http://crdd.osdd.net/raghava/gdoq, has been developed for predicting inhibitors GlmU.

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Inhibitors of bacterial tubulin target bacterial membranes in vivo.

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Inhibitors of bacterial tubulin target bacterial membranes <i>in vivo.</i>

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