Drugs rout MRSA by targeting bad bug enzymes
U.S. researchers may have cracked an antibiotic resistance problem, or at least provided a first step toward its solution. They have discovered antibacterial compounds that are effective in preclinical studies against methicillin-resistant Staphylococcus aureus (MRSA) infections, and that could even reverse resistance, making the bacteria vulnerable to antibiotics again. The research was published in Proceedings of the National Academy of Sciences.
The team started by using computer simulations to find weak points in an enzyme called FPPS, which helps to build bacterial cell walls but is not found in humans, and then looked through libraries of molecules to find some that might target the enzyme. It found a lead that also targeted another enzyme in the same pathway, and used it as a basis for creating a more potent analog. This new compound successfully tackled cultures of MRSA, and worked with and augmented the effects of methicillin. It also showed dramatic effects in infected mice.
"Twenty out of 20 animals survived if they were treated with this drug lead and zero survived if they weren't treated," says Eric Oldfield of the University of Illinois.
MRSA is a term that raises fear in patients, doctors and healthcare administrators alike. Methicillin was launched in 1959, and the first cases of staph infection resistant to methicillin showed up as early as 1961. The term MRSA is now generally used to refer to strains of the bug resistant to all penicillins.
This is a global and growing problem. Between 2003 and 2008 the rate of MRSA infections in U.S. academic hospitals alone doubled, and staph infections now kill more people in the U.S. than HIV/AIDS. This means that there is an unmet need for new drugs to treat both patients and carriers, and a market opportunity for successful companies.
"There's an urgent need for more antibiotics because of drug resistance," says Oldfield. "There are, for example, completely drug-resistant strains of tuberculosis. None of the drugs work against these strains of tuberculosis, and so, if you get it, you die."
While this particular project is a long way from the clinic, it promotes the idea of targeting more than one enzyme to avoid new forms of resistance and circumvent existing routes. There are other potential approaches ongoing, for example Cubist is staying with antibacterials, Pfizer ($PFE), GlaxoSmithKline ($GSK) and NovaDigm are developing MRSA vaccines, and IBM ($IBM) has looked at a semiconductor-based approach.
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