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Volume 23
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Article

Specific Amino Acid Substitutions in OXA-51-Type β-Lactamase Enhance Catalytic Activity to a Level Comparable to Carbapenemase OXA-23 and OXA-24/40

by
Kwan-Wai Chan
1,2,†,
Chen-Yu Liu
2,†,
Ho-Yin Wong
1,
Wai-Chi Chan
1,
Kwok-Yin Wong
1 and
Sheng Chen
2,*
1
State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
2
Department of Infectious Diseases and Public Health, City University of Hong Kong, Kowloon, Hong Kong
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2022, 23(9), 4496; https://doi.org/10.3390/ijms23094496
Submission received: 8 April 2022 / Accepted: 13 April 2022 / Published: 19 April 2022
(This article belongs to the Special Issue Drug Resistance Mechanisms in Bacteria 3.0)
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Abstract

The chromosomal blaOXA-51-type gene encodes carbapenem-hydrolyzing class D β-lactamases (CHDLs), specific variants shown to mediate carbapenem resistance in the Gram-negative bacterial pathogen Acinetobacter baumannii. This study aims to characterize the effect of key amino acid substitutions in OXA-51 variants of carbapenem-hydrolyzing class D β-lactamases (CHDLs) on substrate catalysis. Mutational and structural analyses indicated that each of the L167V, W222G, or I129L substitutions contributed to an increase in catalytic activity. The I129L mutation exhibited the most substantial effect. The combination of W222G and I129L substitutions exhibited an extremely strong catalytic enhancement effect in OXA-66, resulting in higher activity than OXA-23 and OXA-24/40 against carbapenems. These findings suggested that specific arrangement of residues in these three important positions in the intrinsic OXA-51 type of enzyme can generate variants that are even more active than known CHDLs. Likewise, mutation leading to the W222M change also causes a significant increase in the catalytic activity of OXA-51. blaOXA-51 gene in A. baumannii may likely continue to evolve, generating mutant genes that encode carbapenemase with extremely strong catalytic activity.
Keywords: A. baumannii; carbapenem resistance; carbapenem-hydrolyzing class D β-lactamases (CHDLs); OXA-51 variants; structure/function relationship A. baumannii; carbapenem resistance; carbapenem-hydrolyzing class D β-lactamases (CHDLs); OXA-51 variants; structure/function relationship

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MDPI and ACS Style

Chan, K.-W.; Liu, C.-Y.; Wong, H.-Y.; Chan, W.-C.; Wong, K.-Y.; Chen, S. Specific Amino Acid Substitutions in OXA-51-Type β-Lactamase Enhance Catalytic Activity to a Level Comparable to Carbapenemase OXA-23 and OXA-24/40. Int. J. Mol. Sci. 2022, 23, 4496. https://doi.org/10.3390/ijms23094496

AMA Style

Chan K-W, Liu C-Y, Wong H-Y, Chan W-C, Wong K-Y, Chen S. Specific Amino Acid Substitutions in OXA-51-Type β-Lactamase Enhance Catalytic Activity to a Level Comparable to Carbapenemase OXA-23 and OXA-24/40. International Journal of Molecular Sciences. 2022; 23(9):4496. https://doi.org/10.3390/ijms23094496

Chicago/Turabian Style

Chan, Kwan-Wai, Chen-Yu Liu, Ho-Yin Wong, Wai-Chi Chan, Kwok-Yin Wong, and Sheng Chen. 2022. "Specific Amino Acid Substitutions in OXA-51-Type β-Lactamase Enhance Catalytic Activity to a Level Comparable to Carbapenemase OXA-23 and OXA-24/40" International Journal of Molecular Sciences 23, no. 9: 4496. https://doi.org/10.3390/ijms23094496

APA Style

Chan, K.-W., Liu, C.-Y., Wong, H.-Y., Chan, W.-C., Wong, K.-Y., & Chen, S. (2022). Specific Amino Acid Substitutions in OXA-51-Type β-Lactamase Enhance Catalytic Activity to a Level Comparable to Carbapenemase OXA-23 and OXA-24/40. International Journal of Molecular Sciences, 23(9), 4496. https://doi.org/10.3390/ijms23094496

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