University of Connecticut researchers have developed novel antibiotic compounds to target methicillin-resistant Staphylococcus aureus infections, offering a potential new drug in the fight against this pathogen.
Methicillin-resistant Staphylococcus aureus (MRSA) infections and how they evade treatment with antibiotics have been under investigation for years following deadly outbreaks. Now in a new study, a team of researchers has developed experimental antibiotics that have proven effective against the deadly superbug.
A 2013 report from the Centers for Disease Control and Prevention (CDC) on the biggest threats from antibiotic-resistant bacteria notes that there are more than 80,400 severe infections caused by MRSA in the United States each year, resulting in 11,285 deaths. MRSA typically causes skin and wound infections, but when the bacteria move deeper into the body, they can lead to sepsis, pneumonia, and bloodstream infections. These forms of staph infections are harder to treat and more deadly than other strains of the bacteria, as many have developed resistance and no longer respond to treatment with methicillin, typically the first-line antibiotic for S. aureus.
Although skin and soft tissue infections from MRSA can still be treated with other antibiotic compounds, bacteria continue to develop resistance to drugs such as trimethoprim-sulfamethoxazole, creating a growing problem in healthcare.
A new study published in the journal Cell Chemical Biology, though, details the work of researchers at the University of Connecticut, who have developed novel experimental antibiotics effective against trimethoprim-resistant MRSA strains. “Although resistance [to trimethoprim] in the community is generally less than 10% in our local area, resistance elsewhere is climbing,” said co-author and UConn pharmacologist Michael Nailor, PharmD, BCPS-AQ ID, in a university press release, noting that up to 30% of MRSA infections in sub-Saharan Africa no longer respond to trimethoprim. “Additionally, many vulnerable patient populations cannot take trimethoprim-sulfamethoxazole or other generic drugs because of side effects they may cause, and new agents are needed,” according to Dr. Nailor.
The study team of UConn Health and Hartford Hospital researchers based their work on collected strains of trimethoprim-resistant MRSA, and for the first time in the United States, identified the trimethoprim resistance genes dfrG and dfrK from the isolates. Despite their resistance, the bacteria had a weak point—a need for the vitamin B9, or folate, a crucial nutrient for the enzyme pathway needed for the pathogen to grow and survive. Trimethoprim, a dihydrofolate reductase, inhibits the folate biosynthetic pathway when effective. The researchers found resistance to the drug in 6 of the 9 staph strains they studied, showing that the trimethoprim resistance genes are easily transferred between bacteria.
To develop new antifolate antibiotic compounds, the researchers used genomic sequencing to identify the plasmid-encoded resistance genes in their isolates and effectively understand how to target the folate enzyme. By matching molecule to compound, they were able to create potent antifolate agents that showed significant activity against even those resistant MRSA strains.
“One of the most exciting aspect of this work was that we had worked hard to design broadly acting inhibitors against many different resistant forms of the enzymes, and these designs proved very effective against two new enzymes we had never considered or previously studied,” said study author Dennis L. Wright, Ph.D.
The research team designed the new drugs so that S. aureus bacteria will have difficulty developing resistance to the compounds, and is now testing it on isolate samples from around the United States while studying new samples for additional resistance mechanisms.