Β-Lactamases and β-Lactamase Inhibitors in the 21st Century. Issue 18 (23rd August 2019)

• Record Type: Journal Article
• Authors: Tooke, Catherine L.; Hinchliffe, Philip; Bragginton, Eilis C.; Colenso, Charlotte K.; Hirvonen, Viivi H.A.; Takebayashi, Yuiko; Spencer, James
• Is Part Of: Journal of molecular biology. Volume 431:Issue 18(2019)
• Page Start: 3472
• Page End: 3500
• Publication Date: 2019-08-23
• Subjects: CTX-M cefotaximase -- DBO diazabicyclooctane -- ESBL extended spectrum β-lactamase -- KPC Klebsiella pneumoniae carbapenemase -- MBL metallo-β-lactamase -- NDM New Delhi metallo-β-lactamase -- OXA oxacillinase -- PBP penicillin-binding protein -- QM/MM quantum mechanics/molecular mechanics -- SBL serine β-lactamase -- SFX serial femtosecond crystallography -- SHV sulfydryl variant -- TEM Temoneira (β-lactamase) -- VIM Verona imipenemase; β-lactam -- antimicrobial resistance -- carbapenemase -- enzyme mechanism -- metallo-β-lactamase; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2019.04.002
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: The β-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria, β-lactamase enzymes that hydrolyze the amide bond of the four-membered β-lactam ring are the primary resistance mechanism, with multiple enzymes disseminating on mobile genetic elements across opportunistic pathogens such as Enterobacteriaceae (e.g., Escherichia coli ) and non-fermenting organisms (e.g., Pseudomonas aeruginosa ). β-Lactamases divide into four classes; the active-site serine β-lactamases (classes A, C and D) and the zinc-dependent or metallo-β-lactamases (MBLs; class B). Here we review recent advances in mechanistic understanding of each class, focusing upon how growing numbers of crystal structures, in particular for β-lactam complexes, and methods such as neutron diffraction and molecular simulations, have improved understanding of the biochemistry of β-lactam breakdown. A second focus is β-lactamase interactions with carbapenems, as carbapenem-resistant bacteria are of grave clinical concern and carbapenem-hydrolyzing enzymes such as KPC (class A) NDM (class B) and OXA-48 (class D) are proliferating worldwide. An overview is provided of the changing landscape of β-lactamase inhibitors, exemplified by the introduction to the clinic of combinations of β-lactams with diazabicyclooctanone and cyclic boronate serine β-lactamase inhibitors, and of progress and strategies toward clinically useful MBL inhibitors. Despite the long history of β-lactamase research, we contend that issues including continuing unresolved questions around mechanism; opportunities afforded by new technologies such as serial femtosecond crystallography; the need for new inhibitors, particularly for MBLs; the likely impact of new β-lactam:inhibitor combinations and the continuing clinical importance of β-lactams mean that this remains a rewarding research area. Graphical Abstract: Unlabelled Image