Antibiotic resistant pathogenic bacteria are becoming a serious public health concern. In the video below, the director of the Centers for Disease Control speaks for a few moments about the threat it poses to public health. Scientists have now reported some advances in the fight against antibiotic resistance in Cell Chemical Biology. Medicinal chemists working at UConn have created experimental drugs that can kill MRSA, Methicillin-Resistant Staphylococcus aureus, a particularly dangerous form of antibiotic-resistant bacteria that can cause deadly infections of the skin, heart and lung. The researchers targeted the use of vitamin B9 by the bacterium, disrupting it in a way that should be difficult for the bacterium to overcome.
MRSA can be acquired in hospitals or in the community, they are on the rise, and they are very difficult to treat because most strains resistant to common antibiotic therapies. One drug that is used to effectively combat MRSA is trimethoprim-sulfamethoxazole, a useful drug that is both inexpensive and relatively safe. However, it’s no longer working for all cases; MRSA resistant to trimethoprim is becoming more common with as many as 30 percent of sub-Saharan Africa based infections resistant to it, something now also observed in Europe and Asia.
The UConn scientists were aiming to find a way to target MRSA that the bacterium cannot easily adapt to. To test some potential drugs, the researchers gathered trimethoprim-resistant strains of MRSA from UConn Heath and Hartford Hospital to use in their work.
"Although resistance [to trimethoprim] in the community is generally less than 10% in our local area, resistance elsewhere is climbing. 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," explained Dr. Michael Nailor, a UConn pharmacologist co-funded with Hartford Hospital.
The spread of antibiotic resistance was actually observable in the local samples. Six out of nine samples of bacteria that were collected carried trimethoprim resistance genes never before identified in the United States. Resistance to other types of antibiotics like tertracyclin and erythromycin was also observed in various ways throughout the samples. The compounds the research team had made were able to defeat those strains.
"We've actually taken strains [of MRSA] from the clinic and shown our compounds work. We were really happy about these results," said Ph.D. candidate Stephanie Reeve.
"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 Wright.
The researchers targeted the use of vitamin B9, or folate, because it’s critical to an enzyme pathway vital to the survival of MRSA. Trimethoprim is the only antifolate antibiotic, and bacteria have evolved ways to get around it. In this work, the scientists did a thorough analysis of the three-dimensional structure of the folate-using enzyme so it could be efficiently targeted. Their strategy appears to be working well, and they are now getting more samples of MRSA so their new drugs can be further tested.
Dr. Jeffrey Aeschlimann, a UConn Health associate professor of pharmacy practice commented: "We'd like to determine if the resistance mechanisms we discovered in our local MRSA strains are also found in other clinics throughout the United States. We also may find other novel resistance mechanisms. In both cases, we will be able to gain even more valuable information about our how our new antibiotics work against MRSA."
If you would like to know more about how trimethoprim is supposed to work, check out the above video.