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Antimicrobial resistance (AMR) is a serious public health crisis worldwide. The excess and improper use of antibiotics is increasing the number of reported resistant microbial strains, compromising the conventional clinical treatments. The World Health Organization (WHO) has declared AMR a health emergency and has announced that the deaths attributable to AMR every year will be of 10 million in 2050, exceeding all the other major causes of death. To respond to AMR threat, an immediate action is required. Structural insights of key molecular players of AMR are fundamental for a deeper understanding of antimicrobial resistance and for the exploration of alternative therapeutic strategies. A group of six scary nosocomial pathogens is named with the acronym 'ESKAPE' because capable of 'escaping' the biocidal action of antibiotics classified as highly important for human medicine. ESKAPE increase frequency of treatment failures and severity of human infections by adapting to altered environmental conditions and by acquiring resistance determinants [1,2]. Among ESKAPE bacteria, three are most problematic, the highly resistant Gram-negative (Gram -) K. pneumoniae, P. aeruginosa and A. baumannii, typically associated with infections in severely ill hospitalized patients [3]. As in other bacteria, their cell envelope shield is the first line of defence against stress conditions and is crucial to resistance to antibiotics. This complex structure exposes two important barriers: capsule polysaccharides (CPS) and lipopolysaccharides (LPS). We have identified several CPS depolymerases synthesized by K. pneumoniae bacteriophages [4,5,6] and we have shown that they are effective against native capsule of specific clinical K. pneumoniae strains and significantly inhibit Klebsiella-induced mortality in a time-dependent manner. We also proposed the first structural characterization of a CPS depolymerase, named KP32gp38, encoded by a bacteriophage against K. pneumoniae (K-type 21 CPS) [7]. Recently, other phage depolymerases directed against hypervirulent strains (K-type 1 and K-type 2 CPS) of K. pneumoniae have been structurally characterized [8,9]. Structural and functional data on these cell envelope depolymerases will be presented as a tool for novel therapeutic development against AMR.
[1] Mulani et al., “Emerging Strategies to Combat ESKAPE Pathogens in the Era of Antimicrobial Resistance: A Review”, Front Microbiol. 2019, 10:539
[2] De Oliveira et al., “Antimicrobial Resistance in ESKAPE Pathogens”, Clin Microb Rev. 2020, 33
[3] Karakonstantis et al.,“Treatment options for K. pneumoniae, P. aeruginosa and A. baumannii co-resistant to carbapenems, aminoglycosides, polymyxins and tigecycline”, Infection. 2020, 48:835-851
[4] Kȩsik-Szeloch, A. et al., “Characterising the biology of novel lytic bacteriophages infecting multidrug resistant Klebsiella pneumoniae”, Virol. J. 2013, 10, 1–12
[5] Majkowska-Skrobek, G. et al., “Capsule-Targeting Depolymerase, Derived from Klebsiella KP36 Phage, as a Tool for the Development of Anti-Virulent Strategy”, Viruses. 2016, 8, (12)
[6] Grazyna Majkowska-Skrobek et al., “Phage-borne depolymerases decrease Klebsiella pneumoniae resistance to innate defense mechanisms”, Front Microbiol. 2018, Oct 23;9:2517
[7] Squeglia et al., “Structural and Functional Studies of a Klebsiella Phage Capsule Depolymerase Tailspike: Mechanistic Insights into Capsular Degradation”, Structure. 2020, 28(6):613-624
[8] Tu et al., “Structural and biological insights into Klebsiella pneumoniae emphasized textsurface polysaccharide degradation by a bacteriophage K1 lyase: implications for clinical use”, Journal of Biomedical Science. 2022, 29:9
[9] Dunstan et al., Mechanistic Insights into the Capsule-Targeting Depolymerase from a Klebsiella pneumoniae Bacteriophage, American Society for Microbiology. 2021, 9(1):e0102321
