Analysis of a novel class A β-lactamase OKP-B-6 of Klebsiella quasipneumoniae: structural characterisation and interaction with commercially available drugs

• Published in: Memórias do Instituto Oswaldo Cruz Vol. 117; p. e220102
• Main Authors: Bellini, Reinaldo, Guedes, Isabella Alvim, Ciapina, Luciane Prioli, de Vasconcelos, Ana Tereza Ribeiro, Dardenne, Laurent Emmanuel, Nicolás, Marisa Fabiana
• Format: Journal Article
• Language: English; Portuguese
• Published: Instituto Oswaldo Cruz, Ministério da Saúde 01.01.2022
• Subjects: PARASITOLOGY; TROPICAL MEDICINE; structure-based drug design; molecular docking; multitarget antibiotics; OKP-B-6; Klebsiella quasipneumoniae; class A β-lactamase
• ISSN: 0074-0276; 1678-8060; 1678-8060
• DOI: 10.1590/0074-02760220102

BACKGROUNDGram-negative and Gram-positive bacteria produce beta-lactamase as factors to overcome beta-lactam antibiotics, causing their hydrolysis and impaired antimicrobial action. Class A beta-lactamase contains the chromosomal sulfhydryl reagent variable (SHV, point mutation variants of SHV-1), LEN (Klebsiella pneumoniae strain LEN-1), and other K. pneumoniae beta-lactamase (OKP) found mostly in Klebsiella's phylogroups. The SHV known as extended-spectrum β-lactamase can inactivate most beta-lactam antibiotics. Class A also includes the worrisome plasmid-encoded Klebsiella pneumoniae carbapenemase (KPC-2), a carbapenemase that can inactivate most beta-lactam antibiotics, carbapenems, and some beta-lactamase inhibitors. OBJECTIVESSo far, there is no 3D crystal structure for OKP-B, so our goal was to perform structural characterisation and molecular docking studies of this new enzyme. METHODSWe applied a homology modelling method to build the OKP-B-6 structure, which was compared with SHV-1 and KPC-2 according to their electrostatic potentials at the active site. Using the DockThor-VS, we performed molecular docking of the SHV-1 inhibitors commercially available as sulbactam, tazobactam, and avibactam against the constructed model of OKP-B-6. FINDINGSFrom the point of view of enzyme inhibition, our results indicate that OKP-B-6 should be an extended-spectrum beta-lactamase (ESBL) susceptible to the same drugs as SHV-1. MAIN CONCLUSIONSThis conclusion advantageously impacts the clinical control of the bacterial pathogens encoding OKP-B in their genome by using any effective, broad-spectrum, and multitarget inhibitor against SHV-containing bacteria.