β-lactamase-mediated Resistance: A Biochemical, Epidemiological and Genetic Overview

Abstract

Early after the introduction of the first (narrow spectrum) penicillins into clinical use, penicillinase-producing staphylococci replaced (worldwide) the previously susceptible microorganisms. Similarly, the extensive use of broad-spectrum, orally administered β- lactams (like ampicillin, amoxicillin or cefalexin) provided a favorable scenario for the selection of gram-negative microorganisms producing broad spectrum β-lactamases almost 45 years ago. These microorganisms could be controlled by the introduction of the so called "extended spectrum cephalosporins". However, overuse of these drugs resulted, after a few years, in the emergence of extended-spectrum β-lactamases (ESBLs) through point mutations in the existing broad-spectrum β-lactamases, such as TEM and SHV enzymes. Overuse of extended-spectrum β-lactams also gave rise to chromosomal mutations in regulatory genes which resulted in the overproduction of chromosomal AmpC genes, and, in other regions of the world, in the explosive emergence of other ESBL families, like the CTX-Ms. Carbapenems remained active on microorganisms harboring these extended-spectrum β-lactamases, while both carbapenems and fourth generation cephalosporins remained active towards those with derepressed (or the more recent plasmidic) AmpCs. However, microorganisms countered this assault by the emergence of the so called carbapenemases (both serine- and metallo- enzymes) which, in some cases, are actually capable of hydrolyzing almost all β-lactams including the carbapenems. Although all these enzyme families (some of them represented by hundreds of members) are for sure pre-dating the antibiotic era in environmental and clinically significant microorganisms, it was the misuse of these antibiotics that drove their evolution. This paper describes in detail each major class of β-lactamase including epidemiology, genetic, and biochemical evaluations.

Exploring the Landscape of Diazabicyclooctane (DBO) Inhibition: Avibactam Inactivation of PER-2 β-Lactamase

“…The catalytic site of CTX-M-15 is more hydrophilic than the sites of the other two enzymes. Two hydrophobic patches (near Ser70 and the B3-B4 ␤-strand loop and B4 ␤-strand) are present in OXA-48 and PER-2, and these may directly contribute to the similarity of the k 2 values for AVI with PER-2 and OXA-48 (Fig. 4).…”

“…Notably, PER ␤-lactamases are frequently detected in South America (Argentina and Uruguay), as well as in regions of the Middle East. PER-2 is the second most prevalent ESBL (after the pandemic CTX-M) found in Argentina, accounting for up to 10% and 5% of the oxyiminocephalosporin resistance in K. pneumoniae and E. coli, respectively (1,2).…”

OXA β-Lactamases

“…Classes A to C have been well documented as both chromosomally encoded and plasmid-mediated enzymes (2). The class D ␤-lactamases have been much more elusive and, for the most part, were identifiable only as plasmid-encoded ␤-lactamases in Gram-negative bacteria.…”

National sentinel site surveillance for antimicrobial resistance in Klebsiella pneumoniae isolates in South Africa, 2010 - 2012

“…The most frequently detected and clinically important ESBLs belong to the TEM, SHV, and CTX-M families, and K. pneumoniae commonly produces all three groups of enzymes. [2] In the past decade, CTX-M enzymes have emerged as the most prevalent type. There are more than 100 different types, which can be broadly divided into five groups based on their amino-acid identities: CTX-M1, CTX-M2, CTX-M8, CTX-M9 and CTX-M25.…”

“…[2] Of further public health concern are the recent emergence of K. pneumoniae strains capable of producing carbapenem-hydrolysing enzymes and the apparent ease of spread of resistance mechanisms by mobile genetic elements. [2] There are few published reports on national antimicrobial resistance rates of K. pneumoniae in South Africa (SA), with data primarily emanating from the private sector, [3] regional studies with limited numbers of local isolates [1] or certain clinical settings. [4] To date, molecular data on ESBL K. pneumoniae in SA are based on detailed studies of small populations.…”