ANTIMICROBIAL AGENTS

Antimicrobial Agents

Antimicrobial agents or antibiotics are naturally occurring substances produced by microorganisms to inhibit other microorganisms. Synthetic compounds should be referred to as chemotherapeutic agents. Examples are sulphonamides, quinolones, nitrofurans, imidazoles, etc. However, there are semi-synthetic antibiotics which are chemically modified forms of naturally occurring antibiotics. Thus, the term antibiotics is used broadly to describe agents utilized to treat systemic infection.

Types of Antimicrobial Agents

There is a huge diversity of antimicrobial agents. So, it is convenient to classify them according to their mode of action on the site whereupon they act to inhibit microbial growth, especially in human infections. Major types of antibiotics are listed as follows:

A) Antibacterial agents

i) Inhibitors of bacterial cell wall synthesis

Three phases make up the intricate process of cell wall biosynthesis, which involves several different proteins. The three stages are known as the cytoplasmic, membrane-associated, and exocytoplasmic stages [9].

The major antibiotics that interfere with the cytoplasmic stage include D-cycloserine and Fosfomycin. The D-cycloserine targets the enzymes like d-Ala–d-Ala ligase and alanine racemase while the Fosfomycin targets the MurA. An essential part of the bacterial cell wall biosynthesis pathway is the Mur enzymes. It is anticipated that inhibiting these enzymes will severely impair this process, weakening the cell wall and producing bactericidal activity as a result. A broad-spectrum bactericidal antibiotic, fosfomycin is very effective against both Gram-positive and Gram-negative infections, including Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Gram-positive pathogens include Staphylococcus aureus and Enterococcus sp. It inhibits the initial stage of cell wall production by binding to the enzyme UDP-N-acetylglucosamine-3-enolpyruvyl transferase (MurA) and imitating the substrate phosphoenolpyruvate. Likewise, Uridyl peptides (tunicamycin) and Ramoplanin are responsible for interfering with the membrane-associated stage wherein Uridyl peptides target MraY and Ramoplanin targets the MurG and lipid II. Moreover, β-Lactams ( targets PBPs), Glycopeptides ( targets Lipid II, d-Ala–d-Ala terminal), Moenomycin ( targets Transglycosylase), Mannopeptimycins, Lantibiotics (nisin) and Defensin (plectasin) targeting Lipid II and  Bacitracin ( targeting Undecaisoprenyl pyrophosphate) cause interference to the extracytoplasmic stage [9].

The peptidoglycan components of the cell walls of many bacteria, both Gram-positive and Gram-negative, are recycled in large quantities during growth and septation [1]. Currently, beta-lactam antibiotics (like penicillin and cephalosporins) that prevent the production of the peptidoglycan layer and glycopeptide antibiotics (like vancomycin and teicoplanin) that interfere with the assembly of the peptidoglycan precursor lipid II are the main inhibitors of cell wall synthesis.

ii) Inhibitors of bacterial cell membrane

A) Colistin

Bacillus polymyxa produces the polycationic peptide antibiotic known as colistin (Polymyxin E), which was identified in Japan in 1949. Colistin has a bactericidal action by effectively solubilizing the bacterial cell membrane. Only two of the five chemical compounds that make up the polymyxin group—polymyxins A, B, C, D, and E—are utilized in clinical settings: colistin, also known as polymyxin E, and polymyxin B [2, 3]. Colistin is currently thought to be a last line of defense against infections in humans brought on by multidrug-resistant Gram-negative bacteria including Pseudomonas aeruginosa, Acinetobacter baumanni, and Enterobacterales, which produce carbapenemase [4].

Resistance to colistin can be explained by a variety of processes. Until 2015, it was thought to be solely inherited by point mutations in the chromosome. Since LPS is what colistin targets, any change in it will change how colistin functions [5]. Salmonella and Escherichia coli can change LPS by converting lipid A into 4-amino-4-deoxy-L-arabinose (L-Ara4N) and/or phosphoethanolamine (PEtn) [6]. Its production is associated with chromosomal-mediated resistance and requires two-component response regulators, PhoP/PhoQ and as well as sensor kinase systems PmrA/PmrB [6-8]. 

iii) Inhibitors of bacterial protein synthesis

iv) Inhibitors of nucleic acid synthesis

v) Other antibacterial agents

B) Antifungal Agents

C) Antiviral Agents

i) Nucleoside analogue

ii) Non-nucleoside analogue

iii) Inhibitors of viral uncoating

iv) Neuraminidase inhibitors

v) Interferons

vi) Nucleoside and nucleotide reverse transcriptase inhibitors

vii) Non-nucleoside reverse transcriptase inhibitors

D) Antiparasitic Agents

REFERENCES

1. Johnson JW, Fisher JF, Mobashery S. Bacterial cell-wall recycling. Ann N Y Acad Sci. 2013 Jan;1277(1):54-75. doi: 10.1111/j.1749-6632.2012.06813.x. Epub 2012 Nov 16. PMID: 23163477; PMCID: PMC3556187.

2. Falagas M.E., Kasiakou S.K. Colistin: The revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin. Infect. Dis. 2005;40:1333–1341. doi: 10.1086/429323.

3. Gallardo-Godoy A., Muldoon C., Becker B., Elliott A.G., Lash L.H., Huang J.X., Butler M.S., Pelingon R., Kavanagh A.M., Ramu S., et al. Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B. J. Med. Chem. 2016;59:1068–1077. doi: 10.1021/acs.jmedchem.5b01593.

4. Andrade FF, Silva D, Rodrigues A, Pina-Vaz C. Colistin Update on Its Mechanism of Action and Resistance, Present and Future Challenges. Microorganisms. 2020 Nov 2;8(11):1716. doi: 10.3390/microorganisms8111716. PMID: 33147701; PMCID: PMC7692639.

5. Biswas S., Brunel J.M., Dubus J.C., Reynaud-Gaubert M., Rolain J.M. Colistin: An update on the antibiotic of the 21st century. Expert Rev. Anti Infect. Ther. 2012;10:917–934. doi: 10.1586/eri.12.78. 

6. Needham B.D., Trent M.S. Fortifying the barrier: The impact of lipid A remodelling on bacterial pathogenesis. Nat. Rev. Microbiol. 2013;11:467–481. doi: 10.1038/nrmicro3047.

7. Falagas M.E., Rafailidis P.I., Matthaiou D.K. Resistance to polymyxins: Mechanisms, frequency and treatment options. Drug Resist. Updates. 2010;13:132–138. doi: 10.1016/j.drup.2010.05.002. 

8. Olaitan A.O., Morand S., Rolain J.M. Mechanisms of polymyxin resistance: Acquired and intrinsic resistance in bacteria. Front. Microbiol. 2014;5:643. doi: 10.3389/fmicb.2014.00643. 

9. Sarkar, P., Yarlagadda, V., Ghosh, C., & Haldar, J. (2017). A review on cell wall synthesis inhibitors with an emphasis on glycopeptide antibiotics. MedChemComm, 8(3), 516. https://doi.org/10.1039/c6md00585c

10. Kahan F. M., Kahan J. S., Cassidy P. J., Kropp H. Ann. N. Y. Acad. Sci. 1974;235:364–386.