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Antiinfectives targeting enzymes and the proton motive force.

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 ?g/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.

SUBMITTER: Feng X

PROVIDER: S-EPMC4697371 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Antiinfectives targeting enzymes and the proton motive force.

Feng Xinxin X Zhu Wei W Schurig-Briccio Lici A LA Lindert Steffen S Shoen Carolyn C Hitchings Reese R Li Jikun J Wang Yang Y Baig Noman N Zhou Tianhui T Kim Boo Kyung BK Crick Dean C DC Cynamon Michael M McCammon J Andrew JA Gennis Robert B RB Oldfield Eric E

Proceedings of the National Academy of Sciences of the United States of America 20151207 51

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 isoprenoi ...[more]

PMID: 26644565

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Project description:There is considerable interest in improving plant productivity by altering the dynamic responses of photosynthesis in tune with natural conditions. This is exemplified by the 'energy-dependent' form of non-photochemical quenching (qE), the formation and decay of which can be considerably slower than natural light fluctuations, limiting photochemical yield. In addition, we recently reported that rapidly fluctuating light can produce field recombination-induced photodamage (FRIP), where large spikes in electric field across the thylakoid membrane (Δψ) induce photosystem II recombination reactions that produce damaging singlet oxygen (1O2). Both qE and FRIP are directly linked to the thylakoid proton motive force (pmf), and in particular, the slow kinetics of partitioning pmf into its ΔpH and Δψ components. Using a series of computational simulations, we explored the possibility of 'hacking' pmf partitioning as a target for improving photosynthesis. Under a range of illumination conditions, increasing the rate of counter-ion fluxes across the thylakoid membrane should lead to more rapid dissipation of Δψ and formation of ΔpH. This would result in increased rates for the formation and decay of qE while resulting in a more rapid decline in the amplitudes of Δψ-spikes and decreasing 1O2 production. These results suggest that ion fluxes may be a viable target for plant breeding or engineering. However, these changes also induce transient, but substantial mismatches in the ATP : NADPH output ratio as well as in the osmotic balance between the lumen and stroma, either of which may explain why evolution has not already accelerated thylakoid ion fluxes. Overall, though the model is simplified, it recapitulates many of the responses seen in vivo, while spotlighting critical aspects of the complex interactions between pmf components and photosynthetic processes. By making the programme available, we hope to enable the community of photosynthesis researchers to further explore and test specific hypotheses.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'.

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Antiinfectives targeting enzymes and the proton motive force.

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Antiinfectives targeting enzymes and the proton motive force.

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