Using Chemical Probes to Assess the Feasibility of Targeting SecA for Developing Antimicrobial Agents against Gram-Negative Bacteria
| Autor: | Hao Zhang, Chaofeng Dai, Nannan Cao, Krishna Damera, Ying-Hsin Hsieh, Martti Vaara, Hsiuchin Yang, Jianmei Cui, Binghe Wang, Chun Jiang, Jinshan Jin, Arpana S. Chaudhary, Phang C. Tai |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Gram-negative bacteria Membrane permeability 030106 microbiology Microbial Sensitivity Tests Biochemistry environment and public health Article Microbiology 03 medical and health sciences Structure-Activity Relationship Bacterial Proteins Drug Discovery Gram-Negative Bacteria Translocase General Pharmacology Toxicology and Pharmaceutics Enzyme Inhibitors Pharmacology Adenosine Triphosphatases SecA Proteins biology Dose-Response Relationship Drug Molecular Structure Organic Chemistry Antimicrobial biology.organism_classification 3. Good health Anti-Bacterial Agents Multiple drug resistance 030104 developmental biology biology.protein Molecular Medicine bacteria Efflux Bacterial outer membrane Bacteria SEC Translocation Channels |
| Zdroj: | ChemMedChem. 11(22) |
| ISSN: | 1860-7187 |
| Popis: | With the wide-spread emergence of drug resistance, there is an urgent need to search for new antimicrobials, especially those against Gram-negative bacteria. Along this line, the identification of viable targets is a critical first step. SecA is a protein translocase and is commonly believed to be an excellent target for the development of broad-spectrum antimicrobials. In recent years, we have developed three structural classes of SecA inhibitors, which have proven to be very effective against Gram-positive bacteria. However, we have not achieved the same level of success against Gram-negative bacteria, despite the potent inhibition of SecA in enzyme assays by the same inhibitors. In this study, we use representative inhibitors as chemical probes to gain understanding as to why these inhibitors were not effective against Gram-negative bacteria. The results validate our initial postulation that the major difference in effectiveness against Gram-positive and Gram-negative bacteria is in the additional permeability barrier posed by the outer membrane in Gram-negative bacteria. We have also found that expression of efflux pumps, which are responsible for multi-drug resistance, have no effect on the effectiveness of these SecA inhibitors. Identification of an inhibitor-resistant mutant and complementation tests of the plasmids containing secA in a secAts mutant showed that a single secA-azi-9 mutation increased the resistance, providing genetic evidence that SecA indeed is the target of these inhibitors in bacteria. Such results strongly suggest SecA as an excellent target for developing effective antimicrobials against Gram-negative bacteria with the intrinsic ability to overcome MDR. A key future research direction should be the optimization of membrane permeability. |
| Databáze: | OpenAIRE |
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