mutants have cell envelope defects influencing antibiotic resistance and bacteriophage susceptibility.

is a Gram-positive bacterium that is resident to the intestines of animals including humans. is also an opportunistic pathogen that causes multidrug resistant (MDR) infections. Bacteriophages (phages) have been proposed as therapeutics for the treatment of MDR infections, however, an obstacle for phage therapy is the emergence of phage resistance. Despite this, the development of phage resistance can impact bacterial fitness, thus, understanding the molecular basis of fitness costs associated with phage resistance can likely be leveraged as an antimicrobial strategy. We discovered that phage resistant harbor mutations in the cell wall hydrolase gene . SagA cleaves crosslinked peptidoglycan (PG) involved in PG remodeling. We show that mutations in compromise PG hydrolysis rendering them sensitive to β-lactam antibiotics. mutants have cell envelope integrity defects, increased cellular permeability, and aberrant distribution of penicillin binding proteins. This corresponds to a growth defect where cells have abnormal division septa, membrane blebbing, and the formation of mini cells. The dysregulation of the cell envelope in mutants alters the binding of phages to the cell surface. Our data support a model where phage infection of requires phages to localize to sites of peptidoglycan remodeling at the cell poles and division septa. Our findings show that by altering the function of a single PG hydrolase, loses intrinsic β-lactam resistance. This indicates that phage therapy could help revive certain antibiotics when used in combination