13 General introduction et al. 2017). Even before its clinical usage began in the 1940s, resistance to penicillin was observed. This phenomenon was initially detected in bacteria that had been exposed to sublethal doses of penicillin over time. In 1940, Abraham et al. discovered that certain bacteria, like Escherichia coli, produce an enzyme called penicillinase that can destroy penicillin (Abraham and Chain 1940). The clinical impact of resistance became evident as the rate of penicillin resistance in S. aureus rose rapidly, reaching over 80% by the late 1960s (Lowy 2003). This meant that nearly 4 out of 5 patients with S. aureus infections were no longer responsive to the first-choice antibiotic (Lobanovska and Pilla 2017; Lowy 2003). Fortunately, new broad-spectrum antibiotics and resistance inhibitors (e.g., clavulanic acid) were subsequently discovered (Docquier and Mangani 2018). Currently, we have a range of antimicrobial agents from various groups, such as quinolones and lipopeptides, although the development of new antibiotic groups has slowed down (Garcia-Bustos, Cabañero-Navalón, and Salavert Lletí 2022; Ventola 2015). The slow pace of antibiotic development raises concerns, particularly in light of the rapid increase in antibiotic resistance rates over the past two decades, particularly among gram-negative bacteria (Ventola 2015; Plackett 2020; Paterson 2006). Among these, the Enterobacterales order holds significant clinical importance (Paterson and Bonomo 2005). Comprising a large group of gram-negative rod-shaped bacteria, Enterobacterales are commonly found in the human gut and are associated with prevalent bacterial infections, such as biliary and urinary tract infections (Janda and Abbott 2021). Septicaemia caused by Enterobacterales is a frequently encountered and potentially fatal complication if not effectively treated (Bone 1993). While many beta-lactam antibiotics, such as cephalosporins and carbapenems, traditionally exhibit susceptibility against most Enterobacterales, the rising rates of beta-lactam resistance within this bacterial order pose a challenge to treatment and have led to decreasing cure rates (Kang et al. 2005; Pop-Vicas and Opal 2014). A major cause of beta-lactam resistance is the presence of enzymes called betalactamases (D M Livermore 1995). These enzymes diminish the effectiveness of betalactam antibiotics by hydrolysing their molecular structure. Specifically, they break open the beta-lactam ring of the antibiotic, rendering its antimicrobial activity inactive. One example of a beta-lactamase is penicillinase. There exists a wide array of different beta-lactamases, some exerting a greater impact on antibiotic resistance than others. Certain beta-lactamases are capable of hydrolysing only narrow-spectrum antibiotics like penicillin, while others can destroy broad-spectrum antibiotics like cephalosporins and carbapenems. 1
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