Staphylococcus aureus is the S in ESKAPE, an acronym for the six bacteria that are considered the greatest threats to public health by the Infectious Disease Society of America. Like the rest of the ESKAPE pathogens, resistance to the first-line drugs that were once effective against them is widespread. In S. aureus, that resistance is to beta-lactams, a group of drugs that includes penicillin and methicillin.

The Centers for Disease Control and Prevention has classified methicillin-resistant S aureus (MRSA) as a serious health threat to the U.S., and estimates it is responsible for more than 80,000 serious infections and about 11,000 deaths a year.

Now, scientists from Merck Research Laboratories have identified a class of compounds that could re-sensitize MRSA to beta-lactams. They described their work in the March 9, 2016, issue of Science Translational Medicine.

The compounds, which the team has dubbed tarocins because they inhibit the enzyme TarO, did not kill bacteria by themselves. Instead, they weakened the cell wall, allowing beta-lactams to regain the upper hand against MRSA.

The work is an example of taking the synthetic lethal approach that has been successful in identifying certain cancer drugs to the development of antibiotics. (See BioWorld Today, Dec. 7, 2015.).

"It's resetting the clock," Christopher Tan told BioWorld Today, back to the good old days when beta-lactams could treat S aureus.

Tan is director of infectious diseases at Merck Research Laboratories and a co-corresponding author on the paper describing the tarocins.

In their experiments, Tan, his co-corresponding authors Terry Roemer and Jing Su, and their team showed that although tarocins did not by themselves kill MRSA, the effect they had on the bacterial cell wall was enough to re-sensitize MRSA to beta-lactams. Combination treatment with tarocin A2 and the beta-lactam dicloxacillin significantly reduced the bacterial count in MRSA-infected mice, while either tarocin A2 or dicloxacillin alone had no effect.

Helperby Therapeutics Group Ltd. is another company working on developing antibiotic resistance breakers, though in contrast to the tarocins, Helperby's HT-61 has antibiotic activity in its own right.

Previous work on the cellular pathway that TarO is a part of, the wall teichoic acid (WTA) synthesis pathway, had shown that inhibiting certain enzymes in the pathway could re-sensitize S. aureus to streptomycin. (See BioWorld Today, Dec. 7, 2015.)

Tan said that restoring bacterial sensitivity to S. aureus is his team's "first focus." But the possibility that inhibitors of WTA synthesis could restore the activity of multiple classes of antibiotics is an added bonus.

Because the tarocins do not kill bacteria outright, there is less selective pressure to develop resistance against them. Once a combination treatment is used, there is selective pressure to develop resistance, since resistance to the tarocins would also mean renewed resistance to beta-lactams.

Tan acknowledged that "resistance is always going to be an issue – the question is how to address it."

One possibility is the development of more potent inhibitors, and Tan and his colleagues are currently working on that possibility.

In the case of TarO inhibitors, another possibility is to ultimately use tarocin as part of a three-drug combination that targets the synthesis of WTA at both early and late points.

TarO is an enzyme that is responsible for an early step in the synthesis of WTA, which is a major component of the S. aureus cell wall. By itself, inhibiting the early stages of WTA will hobble S. aureus cells, but not kill them.

Inhibiting the later stages, however, has antibiotic activity in its own right, because the intermediates produces by early stage synthesis are toxic to cells.

"If you target the late-stage genes, that would serve as direct antibiotics," Tan said.

In all likelihood, though, that antibiotic would not be a very good one, at least as a monotherapy. Several researchers have described that resistance to late-stage WTA synthesis appears to emerge rapidly in preclinical experiments, findings that would likely be repeated in clinical settings.

A three-way combination of an early stage WTA synthesis inhibitor, a late-stage WTA synthesis inhibitor and one of the beta-lactams, however, could solve the problems that each approach has on its own.

Bacteria that developed resistance to the early stage inhibitor would leave the cells exposed to the buildup of toxic intermediates as a result of the late-stage inhibitor, while resistance to the late-stage inhibitor would leave them vulnerable to beta-lactams.

"You could conceivably be inhibiting any mode of resistance for that particular pathway," Tan said.