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Antiinfectives targeting enzymes and the proton motive force
- Source :
- Feng, X; Zhu, W; Schurig-Briccio, LA; Lindert, S; Shoen, C; Hitchings, R; et al.(2015). Antiinfectives targeting enzymes and the proton motive force. Proceedings of the National Academy of Sciences of the United States of America, 112(51), E7073-E7082. doi: 10.1073/pnas.1521988112. UC San Diego: Retrieved from: http://www.escholarship.org/uc/item/1nx415cg, Proceedings of the National Academy of Sciences of the United States of America, vol 112, iss 51
- Publication Year :
- 2015
- Publisher :
- Proceedings of the National Academy of Sciences, 2015.
-
Abstract
- There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5-2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.
- Subjects :
- Models, Molecular
Staphylococcus aureus
In silico
Drug resistance
Molecular Dynamics Simulation
Biology
Biophysical Phenomena
Clomiphene
Mycobacterium tuberculosis
chemistry.chemical_compound
Rare Diseases
Anti-Infective Agents
Piperidines
Models
Drug Discovery
clofazimine
Tuberculosis
Humans
vacquinol
bedaquiline
Enzyme Inhibitors
Lipid bilayer
Alkyl and Aryl Transferases
Multidisciplinary
Molecular Structure
ATP synthase
Uncoupling Agents
Drug discovery
Molecular
Proton-Motive Force
molecular dynamics simulations
biology.organism_classification
Orphan Drug
Emerging Infectious Diseases
Infectious Diseases
PNAS Plus
Membrane protein
chemistry
Biochemistry
5.1 Pharmaceuticals
Quinolines
biology.protein
Antimicrobial Resistance
Bedaquiline
Infection
Biotechnology
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 112
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....5d374429ad045c4d65ffbe929c55cf5c