Identified a new type of Class C β-lactamases from Pseudomonas aeruginosa

A new work published in the International Journal of Biological Macromolecules by the group led by Dr. Antonio Romero at Centro de Investigaciones Biológicas Margarita Salas (CSIC) and first authored by Francisco Javier Medrano, presents the structure of PIB-1 Pseudomonas aeruginosa β-lactamase, which defines a new type of Class C β-lactamases metal-dependent with the ability to hydrolyze carbapenems.

Antibiotic resistance is one of the most important health concerns nowadays. Bacteria have many mechanisms to evade its action. The β-lactamases are the most important resistance determinants. These enzymes degrade the antibiotics rendering them inactive. Based on their structural and functional characteristics β-lactamases are grouped into four categories (A, B, C, and D). Class A, C, and D are serine-hydrolases that depend on the catalytic serine residue for their activity. In contrast, class B are metallo-hydrolases which need one or two metal ions, usually Zn²⁺.

Medrano et al. have resolved the crystal structures of PIB-1 Pseudomonas aeruginosa chromosomally-encoded β-lactamase, in its apo form and in complex with meropenem and zinc. The analysis of its primary sequence shows that it belongs to the class C β-lactamases, which are cephalosporinases that present a set of highly conserved residues. Surprisingly, the PIB-1 crystal structure shows that although it is a class C β-lactamase, the number of conserved residues is low.

Moreover, functional analysis showed that PIB-1 cannot degrade cephalosporins, the typical substrate of class C β-lactamases, but it degrades carbapenems. Additionally, metal ions, such as Zn²⁺, Ni^2+, and Co²⁺ can increase their activity. These metals do not bind to the active site and can induce the formation of trimers, suggesting that the oligomer is more active than the monomer.

Altogether, results suggest that PIB-1 from Pseudomonas aeruginosa defines a new group inside the class C β-lactamases. Its structure is typical of Class β-lactamases but has a low sequence conservation, different substrate profile, and metal dependence. This indicates that the group of Class C β-lactamases might be more diverse than expected, containing enzymes with substrate profiles and primary structures that differ from those of classical-described - Class C β-lactamases.

Reference: A new type of Class C β-lactamases defined by PIB-1. A metal-dependent carbapenem-hydrolyzing β-lactamase, from Pseudomonas aeruginosa: structural and functional analysis. Francisco Javier Medrano, Sara Hernando-Amado, José Luis Martínez, Antonio Romero (2024) International Journal of Biological Macromolecules, 277:134298, https://doi.org/10.1016/j.ijbiomac.2024.134298