Bacteriophage Resistance Alters Antibiotic-Mediated Intestinal Expansion of Enterococci.
Enterococcus faecalis is a human intestinal pathobiont with intrinsic and acquired resistance to many antibiotics, including vancomycin. Nature provides a diverse and virtually untapped repertoire of bacterial viruses, or bacteriophages (phages), that could be harnessed to combat multidrug-resistant enterococcal infections. Bacterial phage resistance represents a potential barrier to the implementation of phage therapy, emphasizing the importance of investigating the molecular mechanisms underlying the emergence of phage resistance. Using a cohort of 19 environmental lytic phages with tropism against E. faecalis, we found that these phages require the enterococcal polysaccharide antigen (Epa) for productive infection. Epa is a surface-exposed heteroglycan synthesized by enzymes encoded by both conserved and strain-specific genes. We discovered that exposure to phage selective pressure favors mutation in nonconserved epa genes both in culture and in a mouse model of intestinal colonization. Despite gaining phage resistance, epa mutant strains exhibited a loss of resistance to cell wall-targeting antibiotics. Finally, we show that an E. faecalis epa mutant strain is deficient in intestinal colonization, cannot expand its population upon antibiotic-driven intestinal dysbiosis, and fails to be efficiently transmitted to juvenile mice following birth. This study demonstrates that phage therapy could be used in combination with antibiotics to target enterococci within a dysbiotic microbiota. Enterococci that evade phage therapy by developing resistance may be less fit at colonizing the intestine and sensitized to vancomycin, preventing their overgrowth during antibiotic treatment.
['Chatterjee|Anushila|A|', 'Johnson|Cydney N|CN|', 'Luong|Phat|P|', 'Hullahalli|Karthik|K|', 'McBride|Sara W|SW|', 'Schubert|Alyxandria M|AM|', 'Palmer|Kelli L|KL|0000-0002-7343-9271', 'Carlson|Paul E|PE|', 'Duerkop|Breck A|BA|0000-0003-4030-9822']
D000818:Animals D000900:Anti-Bacterial Agents D001435:Bacteriophages D001691:Biological Therapy D013293:Enterococcus faecalis D016984:Enterococcus faecium D005260:Female D016908:Gram-Positive Bacterial Infections D006801:Humans D007422:Intestines D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008826:Microbial Sensitivity Tests D014640:Vancomycin
bacteriophages Enterococcus intestinal colonization dysbiosis antibiotic resistance exopolysaccharide