Drug Combination Cures MRSA Infection While Preventing Development of Resistance

Treatment with a combination comprising the well-known antibiotic cefdinir and the experimental drug TXA709 cured mice of drug-resistant staphylococcal infections while reducing the development of resistance.

The use of combination therapy with synergistic drug partners to treat bacterial infections offers distinct advantages. Among these advantages are (i) a reduction of the drug dose required for efficacy, (ii) a reduced potential for drug-induced toxicity, and (iii) a reduced potential for the emergence of resistance.

In the current study, investigators at Rutgers University (Piscataway, NJ, USA) described the synergistic actions of the third-generation oral cephalosporin, cefdinir, and TXA709, a second-generation FtsZ-targeting prodrug.

Cephalosporins are bactericidal and have the same mode of action as other beta-lactam antibiotics (such as penicillins), but are less susceptible to beta-lactamase enzymes. Cephalosporins kill bacteria by disrupting the synthesis of the peptidoglycan layer forming the bacterial cell wall.

FtsZ is a protein encoded by the ftsZ gene that assembles into a ring at the future site of the septum of bacterial cell division. This is a prokaryotic homologue to the eukaryotic protein tubulin. During cell division, FtsZ is the first protein to move to the division site, and is essential for recruiting other proteins that produce a new cell wall between the dividing cells. FtsZ's role in cell division is analogous to that of actin in eukaryotic cell division, but, unlike the actin-myosin ring in eukaryotes, FtsZ has no known motor protein associated with it.

The investigators reported in the May 9, 2016, online edition of the journal Antimicrobial Agents and Chemotherapy that the active product of TXA709 (TXA707) acted synergistically with cefdinir in vitro against clinical isolates of MRSA, vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA), and linezolid-resistant S. aureus (LRSA). In addition, the combination of TXA707 and cefdinir significantly reduced or eliminated the detectable emergence of resistance relative to TXA707 alone. They also demonstrated synergy in vivo with oral administration of the prodrug TXA709 and cefdinir in mouse models of both systemic and tissue (thigh) infection with MRSA. This synergy reduced the dose of TXA709 required for efficacy by three-fold.

"Current standard-of-care drugs for the treatment of MRSA infections are limited," said senior author Dr. Daniel Pilch, associate professor of pharmacology at Rutgers University. "Furthermore, resistance to these drugs is on the rise, and their clinical effectiveness is likely to diminish in the future. What is also good about this experimental treatment is that both drugs can be taken orally, which means they can be administered on an outpatient basis. All but two of the current antibiotics being used clinically to treat MRSA need to be administered intravenously."

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