Exploring Additional Dimensions of Complexity in Inhibitor Design for Serine β-Lactamases: Mechanistic and Intra- and Inter-molecular Chemistry Approaches

Abstract

As a bacterial resistance strategy, serine β-lactamases have evolved from cell wall synthesizing enzymes known as penicillin-binding proteins (PBP), by not only covalently binding β-lactam antibiotics but, also acquiring mechanisms of deacylating these antibiotics. This critical deacylation step leads to release of hydrolyzed and inactivated β-lactams, thereby providing resistance for the bacteria against these antibiotics targeting the cell wall. To combat β-lactamase-mediated antibiotic resistance, numerous β-lactamase inhibitors were developed that utilize various strategies to inactivate the β-lactamase. Most of these compounds are “mechanism-based” inhibitors that in some manner mimic the β-lactam substrate, having a carbonyl moiety and a negatively charged carboxyl or sulfate group. These compounds form a covalent adduct with the catalytic serine via an initial acylation step. To increase the life-time of the inhibitory covalent adduct intermediates, a remarkable array of different strategies was employed to improve inhibition potency. Such approaches include post-acylation intra- and intermolecular chemical rearrangements as well as affecting the deacylation water. These approaches transform the inhibitor design process from a 3-dimensional problem (i.e., XYZ coordinates) to one with additional dimensions of complexity as the reaction coordinate and time spent at each chemical state need to be taken into consideration. This review highlights the mechanistic intricacies of the design efforts of the β-lactamase inhibitors which so far have resulted in the development of “two generations” and 5 clinically available inhibitors.

Molecular docking, dynamics and free energy analyses of Acinetobacter baumannii OXA class enzymes with carbapenems investigating their hydrolytic mechanisms

“…This life-threatening bacterium causing infectious disease has attracted both the clinical and the commercial sectors, leading to improved understanding of the mechanistic and structural aspects of disease prevalence and infection control [5]. Beta-lactam antibiotics are considered to be an appropriate choice for the treatment of susceptible A.…”

β-lactam/β-lactamase inhibitor combinations: an update

“…6) is a penicillin sulfone inhibitor which has been reported to inhibit multiple class of SBLs. 73 Pattanaik and co-workers reported strong inhibition of SHV-1 and SHV-2 (class A) by LN-1-255 and potentiation of ceftazidime 6 against strains producing TEM, SHV, CTX-M and Sme-1 enzymes. 74 Crystallographic data obtained for SHV-1 suggests that LN-1-255 acylates the enzyme followed by rearrangement to a bicyclic indolizine adduct.…”

Repurposing approved drugs on the pathway to novel therapies

“…For example, one can pair piperacillin with tazobactam, a competitive inhibitor of β‐lactamases that protects the paired antibiotic from degradation. The mechanisms of β‐lactamases and their respective inhibitors that have been successfully combined with antibiotics are discussed in several comprehensive reviews …”