A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA)

Abstract

Staphylococcus aureus is a common human pathogen. Methicillin-resistant Staphylococcus aureus (MRSA) infections pose significant and challenging therapeutic difficulties. MRSA often acquires the non-native gene PBP2a, which results in reduced susceptibility to β-lactam antibiotics, thus conferring resistance. PBP2a has a lower affinity for methicillin, allowing bacteria to maintain peptidoglycan biosynthesis, a core component of the bacterial cell wall. Consequently, even in the presence of methicillin or other antibiotics, bacteria can develop resistance. Due to genes responsible for resistance, S. aureus becomes MRSA. The fundamental premise of this resistance mechanism is well-understood. Given the therapeutic concerns posed by resistant microorganisms, there is a legitimate demand for novel antibiotics. This review primarily focuses on PBP2a scaffolds and the various screening approaches used to identify PBP2a inhibitors. The following classes of compounds and their biological activities are discussed: Penicillin, Cephalosporins, Pyrazole-Benzimidazole-based derivatives, Oxadiazole-containing derivatives, non-β-lactam allosteric inhibitors, 4-(3H)-Quinazolinones, Pyrrolylated chalcone, Bis-2-Oxoazetidinyl macrocycles (β-lactam antibiotics with 1,3-Bridges), Macrocycle-embedded β-lactams as novel inhibitors, Pyridine-Coupled Pyrimidinones, novel Naphthalimide corbelled aminothiazoximes, non-covalent inhibitors, Investigational-β-lactam antibiotics, Carbapenem, novel Benzoxazole derivatives, Pyrazolylpyridine analogues, and other miscellaneous classes of scaffolds for PBP2a. Additionally, we discuss the penicillin-binding protein, a crucial target in the MRSA cell wall. Various aspects of PBP2a, bacterial cell walls, peptidoglycans, different crystal structures of PBP2a, synthetic routes for PBP2a inhibitors, and future perspectives on MRSA inhibitors are also explored.

New Pyrazolyl Thioureas Active against the Staphylococcus Genus

“…The pyrazole scaffold represents a privileged substructure in medicinal chemistry research and a number of pyrazole derivatives have been evaluated as effective compounds in different therapeutic areas [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ], including infectious diseases [ 17 , 18 ] and also against MRSA [ 19 ]. In previous studies, pyrazole derivatives I ( Figure 1 ) showed significative antibacterial activity against Gram-positive antibiotic-resistant strains [ 20 ].…”

Beyond the Wild MRSA: Genetic Features and Phylogenomic Review of mecC-Mediated Methicillin Resistance in Non-aureus Staphylococci and Mammaliicocci

“…The presence of methicillin resistance and resistance to nearly all beta-lactams in staphylococci were historically linked to the acquisition of the mecA gene, which encodes the alternative penicillin-binding protein PBP2a [ 14 ]. However, the frequent association of methicillin resistance in staphylococci, mammaliicocci, and macrococci has now been attributed to the presence of other mec -type genes ( mecB , mecC , and mecD ) ( Table 1 ).…”