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Computer Simulations Aid Search for “Resistance-Resistant” Antibiotics

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Reprint of article originally published January 4, 2016 in UC San Diego Health Sciences News

With the growing threat of drug-resistant bacterial infections, new antibiotics are sorely needed. But we need truly novel classes of antibiotics, not just new versions that kill bacteria the same singular way existing drugs do, says J. Andrew McCammon, PhD, Distinguished Professor of Pharmacology, Chemistry and Biochemistry, and Joseph E. Mayer Chair of Theoretical Chemistry at UC San Diego. We need “resistance-resistant” antibiotics — drugs bacteria won’t easily be able to ignore.

And according to a new study led by McCammon and collaborators, an answer might be right under our noses.

In the study, published in the December 22, 2015 issue of the Proceedings of the National Academy of Sciences, the team tested a collection of chemical compounds — most of which have already in use to treat parasitic infections or other diseases — and found that many are powerful uncouplers. That means that, in addition to the disease-fighting action for which they are known, these drugs can also kill bacteria by blocking the molecular mechanism they employ to generate energy. What’s more, some of these drugs also kill bacteria by inhibiting critical enzymes, such as those involved in bacterial cell wall construction.

“The exciting new thing here is the discovery of a dual mode of action of antibiotics — first, inhibiting enzymes that bacteria need to survive and, second, collapsing the electrical potential across the bacterial cell membrane, which blocks the manufacture of cellular energy,” McCammon says.

In one example, the research team discovered that a widely prescribed fertility drug, clomiphene, can both inhibit bacterial cell walls, busting open bacteria, and uncouple bacteria’s energy-producing system. Clomiphene, they found, effectively kills Staphylococcus aureus, bacteria that can cause invasive, drug-resistant infections.

Curious to see what other known drugs or drug candidates might do the same to bacteria, the researchers turned to computer simulations. Here they discovered that vacquinol, a candidate brain cancer drug, likely acts as an uncoupler in Mycobacterium tuberculosis and inhibits some of the bacterium’s defense mechanisms. Collaborators at the University of Illinois provided experimental confirmation.

“Targeting bacteria with two modes of action reduces the likelihood that they will develop resistance,” says McCammon, who is also a Howard Hughes Medical Institute investigator and a fellow at the San Diego Supercomputer Center.

Link to the full article at News from UC San Diego Health Sciences.

"Computer Simulations Aid Search for “Resistance-Resistant” Antibiotics." UC San Diego Health Sciences News. N.p., 04 Jan. 2016. Web. 01 Feb. 2017.