Dual-Mechanism Antimicrobial Candidate Prevents Drug Resistance by Destroying Microbial DNA

A team of researchers from India recently developed an antimicrobial peptide (AMP)-mimetic drug candidate that displayed the ability to disrupt the structural integrity of bacterial membranes as well as induce the hydrolytic cleavage of bacterial DNA, exerting bacteriocidal activity on various bacterial strains such as MRSA.

The most pressing healthcare-related threat today is the worldwide incidence of drug-resistant microbes – in the World Health Organization’s 2014 Global Report on Antimicrobial Resistance, even last-resort therapeutics have been seen to fail against infections by common bacteria such as Neisseria gonorrhoeae due to widespread drug resistance. AMPs, with their ability to rapidly attack and lyse bacterial membrane via ampiphilic interactions, have been shown to be less readily resisted by microbes and regarded as a potential candidate for next-generation antimicrobials. However, AMPs are rapidly degraded by our enzymes once they enter our body, and are also very expensive to manufacture due to their large structures.

In response to the need for more antimicrobial candidates, Aiyagari Ramesh’s team synthesized a small-molecule AMP analogue which retains the ampiphilic character that is key to its antimicrobial activity, but is not degraded by our enzymes due to its lack of peptide bonds. The molecule attacks bacteria firstly at the cell membrane then subsequently at the DNA. Its positively-charged pyridinium moiety facilitates its rapid approach on the negatively-charged bacterial membrane surface, and upon contact its non-polar hydrocarbon “tail” can puncture the hydrophobic membrane body. Guided by the pyridinium moiety, the molecule then “seeks out” the negatively-charged bacterial DNA and cleaves and destroys it, preventing the bacteria from passing on any genes that may harbour drug-resistant traits.

However given that human cells too have cell membranes, more research needs to be done to ensure that the drug only targets and destroys those of bacteria and other microbial pathogens.

Source: D Thiyagarajan et alChem. Commun., 2014, DOI: 10.1039/c4cc02354d

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Organic chemist and one-time synthetic biologist. Bringing you the latest scoop in chemistry, biomedicine, and materials.