Antibiotic resistance is a major public health problem. Many bacterial infections have become difficult to treat because the microbes responsible have adapted to become resistant to the most effective antibiotics. Methicillin-resistant Staphylococcus aureus, or MRSA, has evolved from a controllable nuisance into a serious public health concern. MRSA is now one of the most common hospital-acquired infections. Recently, new strains have emerged in the community that are capable of causing severe infections in otherwise healthy people.
Digitally colorized scanning electron micrograph of methicillin-resistant Staphylococcus aureus (mustard-colored spheres) and a dead human white blood cell (red). Image credit: NIAID.
In the 1940s, S. aureus infections were treated with compounds called β-lactams (penicillins). These drugs interfere with the synthesis of cell walls to prevent bacteria from growing and reproducing. Bacteria capable of making enzymes that break down β-lactams soon emerged. Second-generation penicillins, such as methicillin, were resistant to those enzymes. However, methicillin-resistant strains were reported soon after the drug’s introduction. These strains had acquired genes from other bacteria that enabled them to produce cell walls even in the presence of β-lactams. Researchers have continued to develop new types of antibiotics to combat MRSA infections, but resistance to many of these have already been reported.
Combinations of antibiotics have had promising results against some microbes. An NIH-funded team led by Dr. Gautam Dantas at Washington University School of Medicine in St. Louis tested a multidrug approach against MRSA. The scientists carefully selected clinically approved drugs that work synergistically. They chose from 3 distinct subclasses of β-lactam compounds that target different aspects of the cell wall synthesis machinery in MRSA: meropenem, piperacillin, and tazobactam (ME/PI/TZ). Results of the study appeared online in Nature Chemical Biology on September 14, 2015.
The scientists began with a MRSA strain that is highly resistant to 23 diverse antibiotics. The ME/PI/TZ trio was more effective against the strain than any of the drugs alone or in pairs. The triple combination also proved effective in the lab against a panel of strains taken from 72 other clinical cases of MRSA.
The researchers next tested the ability of the drug trio to suppress the development of resistance in MRSA. After exposing the bacteria to low doses of the antibiotics for 11 days, they observed no evolution of resistance to ME/PI/TZ. In contrast, the bacteria developed resistance to all the drugs used alone or in pairs within 1–8 days.
Finally, the team tested the drugs in mice infected with MRSA. All mice treated with ME/PI/TZ survived for 6 days after infection, which was comparable to those treated with linezolid, a more expensive drug currently used to treat resistant infections. Blood taken from the mice confirmed that the infection had been eliminated.
“This three-drug combination appears to prevent MRSA from becoming resistant to it,” Dantas says. “We know all bacteria eventually develop resistance to antibiotics, but this trio buys us some time, potentially a significant amount of time.”
More testing will need to be done to assess whether β-lactams can once again prove effective in the clinic against MRSA. Other antibiotics might also be repurposed in similarly designed synergistic combinations.
—by Harrison Wein, Ph.D.