Defining the architecture of KPC-2 β-lactamase: condition sine qua non for resistance

The rise of multi-drug resistance in bacterial pathogens is one of the greatest challenges life sciences are facing nowadays. In the last decade, KPC-2 has earned worldwide attention because of its growing spectrum of resistance towards all classes of β-lactam antibiotics, including carbapenems, our last defence against life-threatening nosocomial infections. A main concern is the speed of KPC-2 in developing resistance, putting at risk the efficacy of the most recent approved carbapenemase inhibitors (covalent inhibitors and BLIP). As a result, new strategies to overcome resistance are urgently required, together with a deep understanding of the inner mechanisms regulating KPC-2.Using HTMD and employing enhanced sampling computational methods together with in vitro mutagenesis studies, we report the discovery of what we have identified as ‘hydrophobic nets’, whose integrity has been found to be necessary for KPC-2 function and resistance. Being detectable throughout the entire structure, these nets are responsible for structure integrity and allosteric regulation via conformational signaling in KPC-2. On the contrary, nets disruption leads to a complete loss of KPC-2 resistance phenotype and recovered β-lactams activity. Finally, these ‘hydrophobic nets’ found to be highly conserved among class A β-lactamases (e.g. TEM-1 and SHV-1), are a promising target for drugdiscoveryand opens new perspectives for future wide-spread treatments against bacterial resistance.

کلیدواژه ها:

KPC-2 ، β-lactamase ، Resistance