Emerging Strategies to Combat β-Lactamase Producing ESKAPE Pathogens

Abstract

Since the discovery of penicillin by Alexander Fleming in 1929 as a therapeutic agent against staphylococci, β-lactam antibiotics (BLAs) remained the most successful antibiotic classes against the majority of bacterial strains, reaching a percentage of 65% of all medical prescriptions. Unfortunately, the emergence and diversification of β-lactamases pose indefinite health issues, limiting the clinical effectiveness of all current BLAs. One solution is to develop β-lactamase inhibitors (BLIs) capable of restoring the activity of β-lactam drugs. In this review, we will briefly present the older and new BLAs classes, their mechanisms of action, and an update of the BLIs capable of restoring the activity of β-lactam drugs against ESKAPE (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) pathogens. Subsequently, we will discuss several promising alternative approaches such as bacteriophages, antimicrobial peptides, nanoparticles, CRISPR (clustered regularly interspaced short palindromic repeats) cas technology, or vaccination developed to limit antimicrobial resistance in this endless fight against Gram-negative pathogens.

Keywords: ESKAPE; antimicrobial resistance; inhibitors; vaccination; β-lactamase.

Figure 1

The chemical structure of the main classes of BLAs. The β-lactam ring is stained green for all these representatives.

Figure 2

Most common mechanisms of β-lactam resistance in ESKAPE pathogens. Figure created with https://biorender.com/.

Figure 3

Ambler classification system of β-lactamases.

Figure 4

CRISPR Cas9 system targeting MGEs as a powerful tool for genomic editing. The Cas9-sgRNA complex recognizes complementary genetic sites with the 5′ end of the sgRNA. The target gene contains a protospacer, immediately followed by an Protospacer Adjacent Motif (PAM), which is mandatory for the recruitment of the CRISPR Cas9 complex. Cas9 is a dual RNA-guided DNA endonuclease that cleaves each of the two strands three nucleotides upstream of the PAM. Subsequently, several DNA repair mechanisms are employed, such as Non-Homologous End Joining (NHEJ) or Homology Directed Repair (HDR), leading to mutations or gene changes, respectively. CRISPR cas9 system can remove some of the key determinants of antibiotic resistance in bacteria, which is why its use has grown spectacularly in recent years. Figure created with https://biorender.com/.