MurE inhibitors as antibacterial agents: a review
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REVIEW ARTICLE
MurE inhibitors as antibacterial agents: a review Niladri Saha1 · Mohammed Afzal Azam1 Received: 23 April 2020 / Accepted: 31 July 2020 © Springer Nature B.V. 2020
Abstract Peptidoglycan, an essential component of the bacterial cell wall plays a critical role in protecting bacteria against osmotic lysis. The ATP-dependent MurC-F ligases are crucial for the early stages of peptidoglycan biosynthesis. MurE ligase is third in the series and catalyzes the addition of l-Lysine (l-Lys) in Gram-positive bacteria or meso-diaminopimelic acid (meso-A2pm) in most Gram-negative bacteria to form UDP-N-acetylmuramoyl-l-Ala-d-Glu-l-Lys/A2pm. The high substrate specific for l-Lys or meso-A2pm makes this enzyme an attractive target for the development of antibacterial agents. Several MurE inhibitors have been reported including phosphinates, peptidosulfonamides, napthylfuran-2-ones, benzene-1,3-dicarboxylic acids, phosphorylatedhydroxyethylamines, natural compounds, 5-benzylidenethiazolidin-4-ones, N-alkyl-2-alkynyl-4(1H)-quinolones, rhodanine substituted d-glutamic acids, 2,5-dimethyl pyrroles, 2,5-disubstitued furans, tetrahydroisoquinolines etc. In the present review we present an update status and structural information of MurE enzyme inhibitors which may be utilized for the design of potent inhibitors against this enzyme. Keywords MurE inhibitors · IC50 · Peptidosulfonamides · Tetrahydroisoquinolines · Antibacterial activity Abbreviations ATP Adenosine triphosphate d-Glu d-Glutamic acid IC50 Half maximal inhibitory concentration l-Ala l-Alanine meso-A2pm meso-Diaminopimelic acid MIC Minimum inhibitory concentration MurE UDP-N-acetylmuramoyl-l-Ala:d-Glu ligase UDP Uridine-5′-diphosphate UDP-MurNAc UDP-N-acetylmuramic acid
Introduction Resistance to antimicrobials agent among the pathogenic bacteria has emerged as a global threat in the past 20 years and has increased in the past decade [1]. The conserved underexploited antibacterial targets has enabled a search for the advent of genomics era especially in the early stage of * Mohammed Afzal Azam [email protected]; [email protected] 1
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India
peptidoglycan synthesis [2]. Peptidoglycan of the bacterial cell wall is a linear polymer of sugars cross-linked by short peptide bridges and plays a critical role in protecting bacteria against osmotic lysis [3]. A series of Mur enzymes (MurC-F) ensures the assembly of the pentapeptide part of the monomer unit. Mur ligases constitute a family of enzymes with common mechanistic and structural features [4]. In spherical Gram-positive bacteria such as the Streptococci and Staphylococci l-lysine residue appears at the third position of the cell wall peptide moiety (UDP-N-acetylmuramoyl-l-Ala-dGlu-l-Lys), whereas in most Gram-negative bacteria such as Escherichia coli and Bacillus subtilis meso-diaminopimelic acid (meso-A2pm) appears at this position (UDP-N-acetylm
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