Carbapenem-resistant Acinetobacter baumannii is responsible for frequent, hard-to-treat and often fatal healthcare-associated infections. Phage therapy, the use of viruses that infect and kill bacteria, is an approach gaining significant clinical interest to combat antibiotic-resistant infections. However, a major limitation is that bacteria can develop resistance against phages. Here, we isolated phages with activity against a panel of A.baumannii strains and focused on clinical isolates AB900 and A9844 and their phages for detailed characterization. As expected, coincubation of the phages with their hosts in vitro resulted in the emergence of phage-resistant bacterial mutants. Genome sequence analysis revealed that phage-resistant mutants harbored loss-of-function mutations in genes from the K locus, responsible for the biosynthesis of the bacterial capsule.Using molecular biology techniques, phage adsorption assays, and quantitative evaluation of capsule production, we established that the bacterial capsule serves as the primary receptor for these phages. As a collateral phenotype of impaired capsule production, the phage-resistant strains could not form biofilms, became fully sensitized to the human complement system, showed increased susceptibility to beta-lactam antibiotics, and became vulnerable to additional phages. Finally, in a murine model of bacteremia, the phage-resistant A.baumannii demonstrated a diminished capacity to colonize blood and solid tissues. This study demonstrates that phages can be used not only for their lytic activity but, if combined with a posteriori knowledge of their receptors and the mechanism of bacterial resistance, for their potential synergy with other antimicrobial agents, thus providing even broader clinical options for phage therapy.
21Carbapenem-resistant Acinetobacter baumannii is responsible for frequent, hard-to-treat and often fatal 22 healthcare-associated infections. Phage therapy, the use of viruses that infect and kill bacteria, is an approach 23 gaining significant clinical interest to combat antibiotic-resistant infections. However, a major limitation is that 24 bacteria can develop resistance against phages. Here, we isolated phages with activity against a panel of A.25 baumannii strains and focused on clinical isolates AB900 and A9844 and their phages for detailed 26 characterization. As expected, coincubation of the phages with their hosts in vitro resulted in the emergence of 27 phage-resistant bacterial mutants. Genome sequence analysis revealed that phage-resistant mutants harbored 28 loss-of-function mutations in genes from the K locus, responsible for the biosynthesis of the bacterial capsule. 29Using molecular biology techniques, phage adsorption assays, and quantitative evaluation of capsule 30 production, we established that the bacterial capsule serves as the primary receptor for these phages. As a 31 collateral phenotype of impaired capsule production, the phage-resistant strains could not form biofilms, became 32 fully sensitized to the human complement system, showed increased susceptibility to beta-lactam antibiotics, 33 and became vulnerable to additional phages. Finally, in a murine model of bacteremia, the phage-resistant A. 34 baumannii demonstrated a diminished capacity to colonize blood and solid tissues. This study demonstrates 35 that phages can be used not only for their lytic activity but, if combined with a posteriori knowledge of their 36 receptors and the mechanism of bacterial resistance, for their potential synergy with other antimicrobial agents, 37 thus providing even broader clinical options for phage therapy. 39 Keywords 40Phage therapy, Acinetobacter baumannii, bacterial capsule, phage receptors, antimicrobial resistance. 41 42 2 Introduction 43In 2019, antimicrobial resistance was listed by the World Health Organization (WHO) as one of the top 44 ten threats to global health (1). Multidrug resistant (MDR) infections are consistently associated with poor clinical 45 outcomes and represent a significant financial burden on the healthcare system (2, 3). Also in 2019, the WHO 46 and Centers for Disease Control and Prevention (CDC) prioritized carbapenem-resistant Acinetobacter 47 baumannii as a pathogen critically requiring research and development of new antimicrobial strategies (4, 5). 48A. baumannii, a gram-negative coccobacillus, is a member of the ESKAPE group of pathogens, which are 49 prominent for causing frequent and hard-to-treat healthcare-associated infections (6). 50As a species, A. baumannii is highly resilient, and capable of surviving for months in biofilms on abiotic 51 surfaces (7, 8). It can cause pneumonia, bacteremia, urinary tract infections, meningitis and wound infections, 52 particularly in the context of intensive care units, and is frequently associated with indwelling med...
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