Cargando…

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

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 r...

Descripción completa

Detalles Bibliográficos
Autores principales: Ambade, Shraddha S., Gupta, Vivek Kumar, Bhole, Ritesh P., Khedekar, Pramod B., Chikhale, Rupesh V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10609489/
https://www.ncbi.nlm.nih.gov/pubmed/37894491
http://dx.doi.org/10.3390/molecules28207008
_version_ 1785128025866633216
author Ambade, Shraddha S.
Gupta, Vivek Kumar
Bhole, Ritesh P.
Khedekar, Pramod B.
Chikhale, Rupesh V.
author_facet Ambade, Shraddha S.
Gupta, Vivek Kumar
Bhole, Ritesh P.
Khedekar, Pramod B.
Chikhale, Rupesh V.
author_sort Ambade, Shraddha S.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-10609489
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-106094892023-10-28 A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA) Ambade, Shraddha S. Gupta, Vivek Kumar Bhole, Ritesh P. Khedekar, Pramod B. Chikhale, Rupesh V. Molecules Review 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. MDPI 2023-10-10 /pmc/articles/PMC10609489/ /pubmed/37894491 http://dx.doi.org/10.3390/molecules28207008 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Ambade, Shraddha S.
Gupta, Vivek Kumar
Bhole, Ritesh P.
Khedekar, Pramod B.
Chikhale, Rupesh V.
A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA)
title A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA)
title_full A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA)
title_fullStr A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA)
title_full_unstemmed A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA)
title_short A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA)
title_sort review on five and six-membered heterocyclic compounds targeting the penicillin-binding protein 2 (pbp2a) of methicillin-resistant staphylococcus aureus (mrsa)
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10609489/
https://www.ncbi.nlm.nih.gov/pubmed/37894491
http://dx.doi.org/10.3390/molecules28207008
work_keys_str_mv AT ambadeshraddhas areviewonfiveandsixmemberedheterocycliccompoundstargetingthepenicillinbindingprotein2pbp2aofmethicillinresistantstaphylococcusaureusmrsa
AT guptavivekkumar areviewonfiveandsixmemberedheterocycliccompoundstargetingthepenicillinbindingprotein2pbp2aofmethicillinresistantstaphylococcusaureusmrsa
AT bholeriteshp areviewonfiveandsixmemberedheterocycliccompoundstargetingthepenicillinbindingprotein2pbp2aofmethicillinresistantstaphylococcusaureusmrsa
AT khedekarpramodb areviewonfiveandsixmemberedheterocycliccompoundstargetingthepenicillinbindingprotein2pbp2aofmethicillinresistantstaphylococcusaureusmrsa
AT chikhalerupeshv areviewonfiveandsixmemberedheterocycliccompoundstargetingthepenicillinbindingprotein2pbp2aofmethicillinresistantstaphylococcusaureusmrsa
AT ambadeshraddhas reviewonfiveandsixmemberedheterocycliccompoundstargetingthepenicillinbindingprotein2pbp2aofmethicillinresistantstaphylococcusaureusmrsa
AT guptavivekkumar reviewonfiveandsixmemberedheterocycliccompoundstargetingthepenicillinbindingprotein2pbp2aofmethicillinresistantstaphylococcusaureusmrsa
AT bholeriteshp reviewonfiveandsixmemberedheterocycliccompoundstargetingthepenicillinbindingprotein2pbp2aofmethicillinresistantstaphylococcusaureusmrsa
AT khedekarpramodb reviewonfiveandsixmemberedheterocycliccompoundstargetingthepenicillinbindingprotein2pbp2aofmethicillinresistantstaphylococcusaureusmrsa
AT chikhalerupeshv reviewonfiveandsixmemberedheterocycliccompoundstargetingthepenicillinbindingprotein2pbp2aofmethicillinresistantstaphylococcusaureusmrsa