Researchers at UCSD, in collaboration with those from several other universities in the U.S. including the University of Illinois and Colorado State University, have discovered a new class of potential antibiotics that may work to disable drug-resistant microbes by targeting cellular membranes. The team published its findings in the “Proceedings of the National Academy of Sciences of the United States of America” on Dec. 22.
The team tested compounds for uncoupler activity using the “Gordon” supercomputer based in the San Diego Supercomputer Center at UCSD. When accompanied by a specific enzyme target, the presence of uncoupler activity presents a step toward the development of antibiotics against drug-resistant bacteria.
Uncouplers are agents that disrupt cells’ synthesis of vital energy molecule adenosine triphosphate, or ATP. They do this by dissociating two essentially coupled processes: the electron transport chain in the membrane and the phosphorylation reactions that use the energy generated by this chain to produce ATP in the cell.
J. Andrew McCammon, contributing author and Distinguished Professor of Pharmacology at UC San Diego, described to the UCSD Guardian the advantage of this possible new class of antibiotics.
“Antibiotics that work by two or more independent mechanisms are less likely to lead to antibiotic-resistant strains of bacteria, so this is likely to be a continuing focus of research,” McCammon said.
The Centers for Disease Control and Prevention recognizes antibiotic resistance as a dangerous, rapidly increasing threat, with more than two million people infected with antibiotic-resistant bacteria each year and 23,000 dying as a result.
In the presence of antibiotics, bacteria naturally undergo genetic changes that can later be transferred to other bacteria; resistance occurs when these changes reduce the effectiveness of a drug. These antibiotics typically target specific enzymes and pathways, allowing the bacteria to undergo minimal changes in order to gain resistance.
Dr. Lici A. Schurig-Briccio, a research scientist at the University of Illinois at Urbana-Champaign and collaborator on the project, discussed how the discovery of an antibiotic with this dual function might impact current perceptions of drugs that attack bacteria on more than one front.
“Our new discovery — showing that many old drugs apart from inhibiting a specific enzyme
activity also act as uncouplers — will change the previous belief that drugs with a
single target are better than drugs targeting multiple pathways,” Schurig-Briccio told the Guardian. “Furthermore, the idea that uncouplers are dangerous — toxic and unsuitable compounds — as antibiotics will be, from now on, questioned.”
According to McCammon, uncouplers lessen the bacteria’s ability to resist drugs by targeting cell membranes’ physical properties.
“This is an additional line of attack against the microbes, in addition to enzyme inhibition,” McCammon said. “If the microbe’s gene for a target enzyme mutates so that the antibiotic no longer inhibits the enzyme, the direct action of the antibiotic against the microbe’s membrane [uncoupling] may still ensure efficacy.”
Those looking to employ uncouplers as antibiotics are proceeding with caution because uncouplers work to disable features common to all cells such as the cells’ “proton motive force” which is responsible for generating energy.
“It’s important that the uncoupling activity not produce side effects in humans,” McCammon said. “Fortunately, it appears that some agents that act as uncouplers in microbial cells are not very active as uncouplers in human cells.”
Schurig-Briccio further clarified how uncouplers remain a promising method of treatment since they can be used to specifically target bacterial cells.
“Uncouplers can be modified in order to target specific cell types,” Schurig-Briccio said. “One way could be by taking advantage of the fact that bacterial cell membrane composition differs from human cell membranes.”