Old and New Beta-Lactamase Inhibitors: Molecular Structure, Mechanism of Action, and Clinical Use

Abstract

The β-lactams have a central place in the antibacterial armamentarium, but the increasing resistance to these drugs, especially among Gram-negative bacteria, is becoming one of the major threats to public health worldwide. Treatment options are limited, and only a small number of novel antibiotics are in development. However, one of the responses to this threat is the combination of β-lactam antibiotics with β-lactamase inhibitors, which are successfully used in the clinic for overcoming resistance by inhibiting β-lactamases. The existing inhibitors inactivate most of class A and C serine β-lactamases, but several of class D and B (metallo-β-lactamase) are resistant. The present review provides the status and knowledge concerning current β-lactamase inhibitors and an update on research efforts to identify and develop new and more efficient β-lactamase inhibitors.

Recommendations to Synthetize Old and New β-Lactamases Inhibitors: A Review to Encourage Further Production

“…Carbapenems, including the longest established imipenem, meropenem, and ertapenem, and the recently developed doripenem, biapenem, panipenem, razupenem, and tomopenem [ 17 ], in addition to resist the inactivating action of the first generations of ESSBLEs, demonstrated their ability to also act as inhibitors for many ESSBLEs [ 18 , 19 , 20 ]. However, the excessive and inappropriate continued use of BLAs has selected, in the past, decade bacteria that is also resistant to carbapenems, including doripenem, ertapenem, imipenem, and meropenem [ 8 , 21 , 22 ], due to their capability to produce both new ESSBLEs capable to also hydrolyse carbapenems and carbapenem-hydrolysing MBLEs of group B [ 23 , 24 , 25 ]. Additionally, the reduction of membrane porins, the improvement in number of efflux pumps [ 23 ], the alteration of PBPs (PBP2 or PBP3), and the hyperexpression of class C AmpCs are supplementary processes involved in the resistance of bacteria to carbapenems [ 26 , 27 ].…”

Antimicrobial Activity of Aztreonam in Combination with Old and New β-Lactamase Inhibitors against MBL and ESBL Co-Producing Gram-Negative Clinical Isolates: Possible Options for the Treatment of Complicated Infections

“…Many BLIs, namely clavulanic acid, sulbactam or tazobactam, are commonly used in clinical practice in association with β-lactams. However, none of them are useful agents against MBL-producers [ 8 ]. Due to the common association of MBL with other β-lactamases (especially ESBL and AmpC), a novel combination including ATM and AVI has been proposed but is not yet commercially available.…”

“…Due to the common association of MBL with other β-lactamases (especially ESBL and AmpC), a novel combination including ATM and AVI has been proposed but is not yet commercially available. AVI is a non-BLI that blocks β-lactamases through a reversible bond and is currently approved in association with ceftazidime for the treatment of complicated urinary tract infections (cUTI), intra-abdominal infections (IAI), pneumonia, and other infections sustained by Gram-negative bacteria [ 8 ]. Ceftazidime–AVI is ineffective against MBL-producers but the broad spectrum of activity of AVI against ESBLs suggested a possible application of its use if combined with ATM.…”

Effects of Itxasol© Components on Gene Expression in Bacteria Related to Infections of the Urinary Tract and to the Inflammation Process

“…Beta lactam that inhibits cell wall synthesis [27] Among the different causes generating resistance are their overuse, which enhances a favorable selective pressure when resistant strains spread and the ease with which resistance factors to treatments are transmitted between them. In addition, another aspect to take into account is bacterial resistance, understood as the ability of the system to return to the initial conditions after having suffered a disturbance to its state; in the case of bacteria, this implies temporary resistance to antibiotics that establishes a series of bacterial subpopulations.…”