Atomic-Resolution Structures and Mode of Action of Clinically Relevant Antimicrobial Peptides

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 May 14

PMID 35562950

Authors

Surajit Bhattacharjya

Sk Abdul Mohid

Anirban Bhunia

Affiliations

Soon will be listed here.

Abstract

Global rise of infections and deaths caused by drug-resistant bacterial pathogens are among the unmet medical needs. In an age of drying pipeline of novel antibiotics to treat bacterial infections, antimicrobial peptides (AMPs) are proven to be valid therapeutics modalities. Direct in vivo applications of many AMPs could be challenging; however, works are demonstrating encouraging results for some of them. In this review article, we discussed 3-D structures of potent AMPs e.g., polymyxin, thanatin, MSI, protegrin, OMPTA in complex with bacterial targets and their mode of actions. Studies on human peptide LL37 and de novo-designed peptides are also discussed. We have focused on AMPs which are effective against drug-resistant Gram-negative bacteria. Since treatment options for the infections caused by super bugs of Gram-negative bacteria are now extremely limited. We also summarize some of the pertinent challenges in the field of clinical trials of AMPs.

Citing Articles

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References

Isaksson J, Brandsdal B, Engqvist M, Flaten G, Mjoen Svendsen J, Stensen W . A synthetic antimicrobial peptidomimetic (LTX 109): stereochemical impact on membrane disruption. J Med Chem. 2011; 54(16):5786-95. DOI: 10.1021/jm200450h. View

Balhuizen M, van Dijk A, Jansen J, van de Lest C, Veldhuizen E, Haagsman H . Outer Membrane Vesicles Protect Gram-Negative Bacteria against Host Defense Peptides. mSphere. 2021; 6(4):e0052321. PMC: 8386409. DOI: 10.1128/mSphere.00523-21. View

Gennaro R, Zanetti M . Structural features and biological activities of the cathelicidin-derived antimicrobial peptides. Biopolymers. 2000; 55(1):31-49. DOI: 10.1002/1097-0282(2000)55:1<31::AID-BIP40>3.0.CO;2-9. View

Sharma P, Sharma N, Mishra P, Joseph J, Mishra D, Garg P . Differential Expression of Antimicrobial Peptides in Streptococcus pneumoniae Keratitis and STAT3-Dependent Expression of LL-37 by Streptococcus pneumoniae in Human Corneal Epithelial Cells. Pathogens. 2019; 8(1). PMC: 6470555. DOI: 10.3390/pathogens8010031. View

Srinivas N, Jetter P, Ueberbacher B, Werneburg M, Zerbe K, Steinmann J . Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa. Science. 2010; 327(5968):1010-3. DOI: 10.1126/science.1182749. View

Bechinger B, Juhl D, Glattard E, Aisenbrey C . Revealing the Mechanisms of Synergistic Action of Two Magainin Antimicrobial Peptides. Front Med Technol. 2022; 2:615494. PMC: 8757784. DOI: 10.3389/fmedt.2020.615494. View

Bhunia A, Ramamoorthy A, Bhattacharjya S . Helical hairpin structure of a potent antimicrobial peptide MSI-594 in lipopolysaccharide micelles by NMR spectroscopy. Chemistry. 2009; 15(9):2036-40. DOI: 10.1002/chem.200802635. View

Mercer D, Robertson J, Miller L, Stewart C, ONeil D . NP213 (Novexatin®): A unique therapy candidate for onychomycosis with a differentiated safety and efficacy profile. Med Mycol. 2020; 58(8):1064-1072. PMC: 7657096. DOI: 10.1093/mmy/myaa015. View

Dash R, Bhattacharjya S . Thanatin: An Emerging Host Defense Antimicrobial Peptide with Multiple Modes of Action. Int J Mol Sci. 2021; 22(4). PMC: 7913509. DOI: 10.3390/ijms22041522. View

10.

Vetterli S, Zerbe K, Muller M, Urfer M, Mondal M, Wang S . Thanatin targets the intermembrane protein complex required for lipopolysaccharide transport in . Sci Adv. 2018; 4(11):eaau2634. PMC: 6235536. DOI: 10.1126/sciadv.aau2634. View

11.

Baker K, Jana B, Hansen A, Nielsen H, Franzyk H, Guardabassi L . Repurposing Azithromycin and Rifampicin Against Gram-Negative Pathogens by Combination With Peptidomimetics. Front Cell Infect Microbiol. 2019; 9:236. PMC: 6615261. DOI: 10.3389/fcimb.2019.00236. View

12.

Brown P, Abdulle O, Boakes S, Divall N, Duperchy E, Ganeshwaran S . Influence of Lipophilicity on the Antibacterial Activity of Polymyxin Derivatives and on Their Ability to Act as Potentiators of Rifampicin. ACS Infect Dis. 2021; 7(4):894-905. PMC: 8138958. DOI: 10.1021/acsinfecdis.0c00917. View

13.

Lazzaro B, Zasloff M, Rolff J . Antimicrobial peptides: Application informed by evolution. Science. 2020; 368(6490). PMC: 8097767. DOI: 10.1126/science.aau5480. View

14.

Zeth K, Sancho-Vaello E . Structural Plasticity of LL-37 Indicates Elaborate Functional Adaptation Mechanisms to Bacterial Target Structures. Int J Mol Sci. 2021; 22(10). PMC: 8156758. DOI: 10.3390/ijms22105200. View

15.

Bhunia A, Domadia P, Torres J, Hallock K, Ramamoorthy A, Bhattacharjya S . NMR structure of pardaxin, a pore-forming antimicrobial peptide, in lipopolysaccharide micelles: mechanism of outer membrane permeabilization. J Biol Chem. 2009; 285(6):3883-3895. PMC: 2823531. DOI: 10.1074/jbc.M109.065672. View

16.

Leontiadou H, Mark A, Marrink S . Antimicrobial peptides in action. J Am Chem Soc. 2006; 128(37):12156-61. DOI: 10.1021/ja062927q. View

17.

Zasloff M . Antimicrobial Peptides of Multicellular Organisms: My Perspective. Adv Exp Med Biol. 2019; 1117:3-6. DOI: 10.1007/978-981-13-3588-4_1. View

18.

Bhattacharjya S . NMR Structures and Interactions of Antimicrobial Peptides with Lipopolysaccharide: Connecting Structures to Functions. Curr Top Med Chem. 2015; 16(1):4-15. DOI: 10.2174/1568026615666150703121943. View

19.

Sinha S, Dhanabal V, Sperandeo P, Polissi A, Bhattacharjya S . Linking dual mode of action of host defense antimicrobial peptide thanatin: Structures, lipopolysaccharide and LptA binding of designed analogs. Biochim Biophys Acta Biomembr. 2021; 1864(3):183839. DOI: 10.1016/j.bbamem.2021.183839. View

20.

Nguyen L, Haney E, Vogel H . The expanding scope of antimicrobial peptide structures and their modes of action. Trends Biotechnol. 2011; 29(9):464-72. DOI: 10.1016/j.tibtech.2011.05.001. View