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Preprint Letter: Bacteriophages and Colistin: A Promising Therapy and...
Anionic Phage followed by cationic antimicrobial peptide Colistin Sequential Therapy (PCST) is promising for medical applications. Furthermore, its mechanism reveals important unconsidered factors of plasmid-mediated mobile colistin resistance (mcr) genes and colistin resistance surveillance. In brief, the evolution of mcr genes is more consistent with an ancient adaptation against cationic phages, and cationic antimicrobial peptides, instead of multiple evolutionary events triggered by the use of colistin (a last resort antimicrobial) for non-therapeutic applications. Key evidence was revealed during the development of PCST. Phages a ctive against bacteria producing phosphoethanolamine transferases codified by an mcr gene were isolated. The mcr genes confer resistance to colistin by adding a positive residue to the lipopolysaccharide (LPS) of the bacteria’s external membrane [1]. Colistin, a cationic antimicrobial peptide, is repealed, and thus bacteria become resistant to it. This principle is also applied to certain cationic phages. To develop PCST, an anionic phage effective against MCR-producing bacteria was selected. As expected, bacteria evolved resistance by turning their LPS more negative after this anionic phage application. Therefore, these bacteria became sensitive to colistin again [2,3]. This therapy is simple, effective, and biomimetic. Additionally, it reveals a possible phenomenon of serendipitous adaptation to colistin. The above experimental evidence suggests the implication of phages and peptides as ancestral selective forces for mcr genes evolution. Hao., et al., 2019, also found these interactions in clinical settings and discuss their results from a medical standpoint [4]. Khedher., et al, 2020, present an extensive bioinformatic analysis of bacterial genomes and suggest mcr genes; ecological role as an adaptation against phage and antimicrobial peptides [5]. This view could explain why the mcr-9 gene is unable to confer resistance to colistin on its own [6]. It also aligns with data reporting no significant differences in the prevalence of mcr between environments exposed to colistin and environments not exposed to colistin, and with other intriguing observations during epidemiological studies.
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