These compounds act as suicide inhibitors, covalently bonding the Ser residue in the active site of the ОІ-lactamase and permanently inactivating the enzyme. In order to overcome the serine ОІ-lactamases-mediated resistance, several inhibitors have been introduced in the clinic for a long time. All of them share three sequence motifs common also to PBPs, but the class A enzymes are characterized by the presence of a conserved Glu residue in the so-called О©-loop involved in the activation of the catalytic water molecule during deacylation, whereas class C enzymes are characterized by a conserved Tyr residue replacing the corresponding Ser residue of class A in motif II, and class D enzymes have a unique N-carboxylated Lys residue in motif I. Serine ОІ-lactamases can be divided in three classes based on sequence identity. The first group evolved from the penicillin-binding proteins (PBPs), the targets of ОІ-lactam antibiotics, and their mechanism of action proceeds via the same acylation/deacylation mechanism involving a Ser residue in the active site. This last group hosts a Zn ion in the active site, which is coordinated to metal ligating amino acids, and the cleavage of the ОІ-lactam ring proceeds with the aid of polarized water molecules. Based on their mechanism of action, they can be divided in two principal groups: serine ОІ-lactamases and metallo ОІ-lactamases. These enzymes catalyze the cleavage of the ОІ-lactam ring responsible for the bactericidal activity of these antibiotics. The most important mechanism of resistance against this class of molecules is the activity of ОІ-lactamases, a family of hydrolytic enzymes whose genes are mainly located on easily transferable plasmids and, as a consequence, have rapidly disseminated through the different bacteria species. О’-lactams are still the most widely used class of antibiotics, because of their pharmacological advantages such as potent activity combined with low toxicity, and also for their ease of delivery and low production costs. Therefore, on one side, there is an absolute need for coordinated action of all countries to avoid the spread of antibiotic resistance on the other hand, there is the urgency to focus the research either on the development of new antimicrobial molecules able to escape to the mechanisms of antibiotic resistance in bacteria, or to counteract the resistance against the most commonly used antibiotics. Despite many initiatives to address this issue, new resistance mechanisms are emerging and spreading globally. However, since 1970s, the decline in the discovery of novel antimicrobial molecules and the irresponsible misuse/overuse of traditional antibiotics has led to the selection of multidrug resistant bacteria (the so-called вЂњsuperbugsвЂќ) that are now considered as a main threat for global public health. Nevertheless, the impact of this phenomenon in clinics was probably underestimated, at least until the вЂњgolden age of antibioticsвЂќ has continued.

When the use of antibiotics was diffused worldwide, the presence of resistant strains of bacteria able to inactivate these drugs became more and more evident. Indeed, already in 1940, only about a decade after the discovery of penicillin and even before its introduction in clinics, two researchers found a bacterial enzyme able to inactivate it.

The problem of the antibiotic resistance is as old as the discovery of antibiotics themselves. The detailed analysis of the complexes obtained by these simulations suggests possible hints to modulate the affinity of this compound towards these enzymes, in order to develop new derivatives with improved features to escape to degradation. The results of the simulations, performed by using a covalent docking approach, has shown that this compound, although able to bind the selected ОІ-lactamases, has a different predicted binding score for the two ОІ-lactam rings, suggesting that one of them could be more resistant to the attack of these enzymes and stay available to perform its bactericidal activity. We have applied a computational approach to predict the interactions between a new cephalosporin derivative containing an additional ОІ-lactam ring with different substituents, and several serine ОІ-lactamases representative of the different classes of this family of enzymes. The researchers worldwide are actively involved in the search for new classes of antibiotics, and for the modification of known molecules in order to face this threatening problem. One of the main concerns of the modern medicine is the frightening spread of antimicrobial resistance caused mainly by the misuse of antibiotics.

Han 2010 pbp3 pseudomonas