Identification of Cell Wall Binding Domains and Repeats in Phage Endolysins: A Molecular and Diversity Analysis

Overview

Journal Biochem Biophys Rep

Specialty Biochemistry

Date 2024 Nov 1

PMID 39483175

Authors

Tahsin Khan

Shakhinur Islam Mondal

Araf Mahmud

Daniyal Karim

Lorraine A Draper

Colin Hill

Abul Kalam Azad

Arzuba Akter

Affiliations

Soon will be listed here.

Abstract

(pneumococcus) is a multidrug-resistant pathogen associated with pneumonia, otitis media, meningitis and other severe complications that are currently a global threat to human health. The World Health Organization listed as the fourth of twelve globally prioritized pathogens. Identifying alternatives to antibiotic therapies is urgently needed to combat . Bacteriophage-derived endolysins can be used as alternative therapeutics due to their bacterial cell wall hydrolyzing capability. In this study, phage genomes were screened to create a database of endolysins for molecular modelling and diversity analysis of these lytic proteins. A total of 89 lytic proteins were curated from 81 phage genomes and categorized into eight groups corresponding to their different enzymatically active (EAD) domains and cell wall binding (CBDs) domains. We then constructed three-dimensional structures that provided insights into these endolysins. Group I, II, III, V, and VI endolysins showed conserved catalytic and ion-binding residues similar to existing endolysins available in the Protein Data Bank. While performing structural and sequence analysis with template lysin, an additional cell wall binding repeat was observed in Group II lysin, which was not previously known. Molecular docking performed with choline confirmed the existence of this additional repeat. Group III endolysins showed 99.16 % similarity to LysME-EF1, a lysin derived from . Furthermore, the comparative computational analysis revealed the existence of CBDs in Group III lysin. This study provides the first insight into the molecular and diversity analysis of phage endolysins that could be valuable for developing novel lysin-based therapeutics.

References

Mondal S, Akter A, Draper L, Ross R, Hill C . Characterization of an Endolysin Targeting That Affects Spore Outgrowth. Int J Mol Sci. 2021; 22(11). PMC: 8199566. DOI: 10.3390/ijms22115690. View

Zhou B, Zhen X, Zhou H, Zhao F, Fan C, Perculija V . Structural and functional insights into a novel two-component endolysin encoded by a single gene in Enterococcus faecalis phage. PLoS Pathog. 2020; 16(3):e1008394. PMC: 7098653. DOI: 10.1371/journal.ppat.1008394. View

Dereeper A, Guignon V, Blanc G, Audic S, Buffet S, Chevenet F . Phylogeny.fr: robust phylogenetic analysis for the non-specialist. Nucleic Acids Res. 2008; 36(Web Server issue):W465-9. PMC: 2447785. DOI: 10.1093/nar/gkn180. View

Frieri M, Kumar K, Boutin A . Antibiotic resistance. J Infect Public Health. 2016; 10(4):369-378. DOI: 10.1016/j.jiph.2016.08.007. View

Tommasi R, Brown D, Walkup G, Manchester J, Miller A . ESKAPEing the labyrinth of antibacterial discovery. Nat Rev Drug Discov. 2015; 14(8):529-42. DOI: 10.1038/nrd4572. View

Hanlon G . Bacteriophages: an appraisal of their role in the treatment of bacterial infections. Int J Antimicrob Agents. 2007; 30(2):118-28. DOI: 10.1016/j.ijantimicag.2007.04.006. View

Sanz J, Diaz E, Garcia J . Studies on the structure and function of the N-terminal domain of the pneumococcal murein hydrolases. Mol Microbiol. 1992; 6(7):921-31. DOI: 10.1111/j.1365-2958.1992.tb01542.x. View

van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark A, Berendsen H . GROMACS: fast, flexible, and free. J Comput Chem. 2005; 26(16):1701-18. DOI: 10.1002/jcc.20291. View

Loeffler J, Fischetti V . Synergistic lethal effect of a combination of phage lytic enzymes with different activities on penicillin-sensitive and -resistant Streptococcus pneumoniae strains. Antimicrob Agents Chemother. 2002; 47(1):375-7. PMC: 149014. DOI: 10.1128/AAC.47.1.375-377.2003. View

10.

Black R, Cousens S, Johnson H, Lawn J, Rudan I, Bassani D . Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet. 2010; 375(9730):1969-87. DOI: 10.1016/S0140-6736(10)60549-1. View

11.

Bakir M, Yagci A, Ulger N, Akbenlioglu C, Ilki A, Soyletir G . Asymtomatic carriage of Neisseria meningitidis and Neisseria lactamica in relation to Streptococcus pneumoniae and Haemophilus influenzae colonization in healthy children: apropos of 1400 children sampled. Eur J Epidemiol. 2002; 17(11):1015-8. DOI: 10.1023/a:1020021109462. View

12.

Bateman A, Rawlings N . The CHAP domain: a large family of amidases including GSP amidase and peptidoglycan hydrolases. Trends Biochem Sci. 2003; 28(5):234-7. DOI: 10.1016/S0968-0004(03)00061-6. View

13.

Diez-Martinez R, de Paz H, Garcia-Fernandez E, Bustamante N, Euler C, Fischetti V . A novel chimeric phage lysin with high in vitro and in vivo bactericidal activity against Streptococcus pneumoniae. J Antimicrob Chemother. 2015; 70(6):1763-73. DOI: 10.1093/jac/dkv038. View

14.

Mondal S, Draper L, Ross R, Hill C . Bacteriophage endolysins as a potential weapon to combat infection. Gut Microbes. 2020; 12(1):1813533. PMC: 7524323. DOI: 10.1080/19490976.2020.1813533. View

15.

Low L, Yang C, Perego M, Osterman A, Liddington R . Role of net charge on catalytic domain and influence of cell wall binding domain on bactericidal activity, specificity, and host range of phage lysins. J Biol Chem. 2011; 286(39):34391-403. PMC: 3190764. DOI: 10.1074/jbc.M111.244160. View

16.

Bogaert D, de Groot R, Hermans P . Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect Dis. 2004; 4(3):144-54. DOI: 10.1016/S1473-3099(04)00938-7. View

17.

Nathan C, Cars O . Antibiotic resistance--problems, progress, and prospects. N Engl J Med. 2014; 371(19):1761-3. DOI: 10.1056/NEJMp1408040. View

18.

Nelson D, Loomis L, Fischetti V . Prevention and elimination of upper respiratory colonization of mice by group A streptococci by using a bacteriophage lytic enzyme. Proc Natl Acad Sci U S A. 2001; 98(7):4107-12. PMC: 31187. DOI: 10.1073/pnas.061038398. View

19.

Payne D, Gwynn M, Holmes D, Pompliano D . Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2006; 6(1):29-40. DOI: 10.1038/nrd2201. View

20.

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View