Tackling the Antibiotic Resistance Caused by Class A β-Lactamases through the Use of β-Lactamase Inhibitory Protein

Abstract

β-Lactams are the most widely used and effective antibiotics for the treatment of infectious diseases. Unfortunately, bacteria have developed several mechanisms to combat these therapeutic agents. One of the major resistance mechanisms involves the production of β-lactamase that hydrolyzes the β-lactam ring thereby inactivating the drug. To overcome this threat, the small molecule β-lactamase inhibitors (e.g., clavulanic acid, sulbactam and tazobactam) have been used in combination with β-lactams for treatment. However, the bacterial resistance to this kind of combination therapy has evolved recently. Therefore, multiple attempts have been made to discover and develop novel broad-spectrum β-lactamase inhibitors that sufficiently work against β-lactamase producing bacteria. β-lactamase inhibitory proteins (BLIPs) (e.g., BLIP, BLIP-I and BLIP-II) are potential inhibitors that have been found from soil bacterium Streptomyces spp. BLIPs bind and inhibit a wide range of class A β-lactamases from a diverse set of Gram-positive and Gram-negative bacteria, including TEM-1, PC1, SME-1, SHV-1 and KPC-2. To the best of our knowledge, this article represents the first systematic review on β-lactamase inhibitors with a particular focus on BLIPs and their inherent properties that favorably position them as a source of biologically-inspired drugs to combat antimicrobial resistance. Furthermore, an extensive compilation of binding data from β-lactamase–BLIP interaction studies is presented herein. Such information help to provide key insights into the origin of interaction that may be useful for rationally guiding future drug design efforts.

Identification of Benzyloxy Carbonimidoyl Dicyanide Derivatives as Novel Type III Secretion System Inhibitors via High-Throughput Screening

“…Genome sequence analysis subsequently revealed a potential β -lactamase gene named penAC in MH21, which had 39.8% identity and 83.0% coverage with the β -lactamase gene penP in Bacillus subtilis (GenBank accession BG11016). Further phylogenetic analysis ( Figure S2 ) and conserved structure analysis ( Table S2 ) revealed that PenAC belongs to β -lactamase class A (Ambler, 1980; Matagne et al, 1999; Eiamphungporn et al, 2018). In addition, mutation of penAC in A. citrulli MH21 led to loss of ampicillin resistance ( Figures S1A, B ), suggesting that PenAC is indeed a β -lactamase.…”

Comprehensive study of antimicrobial susceptibility pattern and extended spectrum beta-lactamase (ESBL) prevalence in bacteria isolated from urine samples

“…Of these mechanisms, the production of B-lactamases is the most prevalent source of resistance to β-lactam antibiotics which are produced by both Gram-positive (extracellularly) and Gram-negative (in the Periplasmic space) bacteria. These enzymes are able to make the β-lactam antibiotics inactive by binding covalently to their carbonyl section and hydrolyzing the b-lactam ring thus enabling β-lactam resistance 6 , 7 .…”

Antibiotic Resistance Profile and Clonality of E. coli Isolated from Water and Paediatric Stool Samples in the North-West, Province South Africa

“…This study, therefore, recommends the continuous monitoring of antibiotic-resistant microorganisms in humans and water. Detection ESBLs gene in the study ESBL-positive E. coli strains are highly resistant to an array of antibiotics and infections caused by these strains are difficult to treat 71 . In the present study, ESBL genes were found in a considerable proportion of the pathotypes screened.…”