AUTHOR=García-Cruz Juan Carlos , Rebollar-Juarez Xareni , Limones-Martinez Aldo , Santos-Lopez Cristian Sadalis , Toya Shotaro , Maeda Toshinari , Ceapă Corina Diana , Blasco Lucia , Tomás María , Díaz-Velásquez Clara Estela , Vaca-Paniagua Felipe , Díaz-Guerrero Miguel , Cazares Daniel , Cazares Adrián , Hernández-Durán Melisa , López-Jácome Luis Esaú , Franco-Cendejas Rafael , Husain Fohad Mabood , Khan Altaf , Arshad Mohammed , Morales-Espinosa Rosario , Fernández-Presas Ana María , Cadet Frederic , Wood Thomas K. , García-Contreras Rodolfo 

TITLE=Resistance against two lytic phage variants attenuates virulence and antibiotic resistance in Pseudomonas aeruginosa

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 13 - 2023

YEAR=2024

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2023.1280265

DOI=10.3389/fcimb.2023.1280265

ISSN=2235-2988

ABSTRACT=Bacteriophage therapy is becoming part of mainstream Western medicine since antibiotics of clinical use tend to fail. It involves applying lytic bacteriophages that self-replicate and induce cell lysis, thus killing their hosts. Nevertheless, bacterial killing promotes the selection of resistant phages; hence, phage combinations (cocktails) are administered instead of single phages, since the probability of simultaneously selecting resistance to all the used phages is very low. A decrease in bacterial virulence or antibiotic resistance sometimes accompanies phage resistance. In this work, we studied the lytic phage φDCL-PA6 and its variant φDCL-PA6, which differs from the original by only two amino acids: one in the baseplate wedge subunit and another in the tail fiber protein.According to genomic data and cross-resistance experiments, these changes may promote the change of the phage receptor from the O-antigen to the core lipopolysaccharide. Interestingly, the host range of the two phages differs as determined against the Pseudomonas aeruginosa reference strains PA14 and PAO1 and against nine multidrug-resistant isolates from ventilatorassociated pneumonia. Resistant mutants against each phage were isolated for PA14 and two clinical strains. We show that phage resistance impacts virulence factor production. Specifically, phage resistance led to decreased biofilm formation, swarming, and type III secretion; therefore, the virulence towards Galleria mellonella was dramatically attenuated. Furthermore, antibiotic resistance decreased for one clinical strain. Our study highlights important potential advantages of phage therapy´s evolutionary impact that may be exploited to generate robust therapy schemes.