Antibiotic resistance is a global problem, alarmingly increasing year by year: several health organizations, including WHO, agree that the spread of multi-resistant bacteria will likely cause more than 10 millions deaths per year by 2050, unless some concrete action is taken. The scientific community has to face a desperate race to find new molecules that can replace the old, non-effective ones and guarantee efficient treatments for bacterial infections. In this perspective, it is fundamental to exploit the molecular mechanisms that allow microbes to develop resistance: this knowledge would allow to inspire new strategies to increase the activity of current treatments, and to drive the drug design process towards new generations of antibiotics.<br/><br/>Carbapenems represent the latest generation of β-lactam antibiotics, effective against a broad spectrum of microbial infections. Similar to penicillins and cephalosporins, they target penicillin-binding proteins and inhibit cell wall synthesis. However, carbapenem resistance has been rapidly spreading, causing a dramatic reduction in treatment options. Mainly, this is caused by expression of Metallo-β-Lactamases (MBLs): among them, the New Delhi MBL (NDM-1) has shown the fastest and largest geographical spread, with 16 alleles spanning over 70 countries.<br/><br/>It was recently demonstrated how membrane-anchoring of a lipidated version of NDM-1 is able to protect this MBL from zinc starvation, which is the usual body response to the rise of NDM-1. In the present study, we investigate the affinity between NDM-1 and bacterial membranes by means of molecular dynamics (MD). The simulations show how the catalytic site, despite playing no role in protein-membrane direct interaction, is fundamental for long-range membrane recognition. In particular, the positive electrostatics determined by the zinc ions is able to drive an association to negatively charged lipids (cardiolipins in particular): this event triggers the membrane recognition, hence causing the anchoring event. The anchoring mode suggests that the catalytic site is not hindered by the membrane, and can therefore continue to perform the hydrolysis of carbapenems: by comparing the behavior of NDM1 with BcII, another well-known enzyme of the same class, we suggest that the action of the metal chelators is reduced by the stabilization of the catalytic site that occurs upon membrane binding.

Exploiting the role of membrane anchoring on the peculiar biological behaviour of multi-drug resistant enzyme New Delhi metallo-β-lactamase 1

256th National Meeting (2018)

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