Lytic bacteriophages as alternative to overcoming antibiotic-resistant biofilms formed by clinically significant bacteria

Bacterial infections are a major public health threat, with a substantial global burden of ∼5 million deaths in 2019, of which ∼1.27 million were attributed to antibiotic resistance. The formation of bacterial biofilms has significantly enhanced bacterial resistance to antibiotics. Worse still, it increases overall bacterial pathogenesis, contributing to inflammation and potentially to carcinogenesis in humans. Biofilm is implicated in approximately 65% of all bacterial infections and 78.2% chronic wound infections. Alarmingly, about 100–1000-fold increase in antibiotic concentration is required to eradicate bacteria within biofilms, further compromising the health of already ill-patients. Therefore, it is imperative to explore potential antibiofilm agents, especially ones with novel mechanisms of action, to clinically manage inpatient biofilms. Bacteriophage (phage) use is a promising evolutionary approach but is also challenged with potential resistance. Bacteria have developed several antiphage defense mechanisms, some of which exhibit synergistic antiphage activity. In this review, we provide several lines of evidence supporting the efficacy of phages against antibiotic-resistant clinical biofilm-forming bacteria. Observations reveal that phage enzymes disrupt biofilm structural components (e.g., EPS, pectate, and hyaluronic acid) and pave the way for phage infection of naked bacterial cells. We further provide insights into the recent advancements in phage use against biofilm-associated antibiotic-resistant bacteria in patients. Current knowledge shows that phages are rapidly evolving and counteracting antiphage bacterial mechanisms. Here, future perspectives to enhance phages efficacy against biofilm resistance are provided to establish their clinical antibiofilm application. Enhancing the clinical application of phages against biofilms requires addressing bacterial host biofilm resistance and optimizing strategies accordingly. Beyond phage cocktail and phage genetic engineering, conjugating phages with antimicrobial agents (eg., antimicrobial peptides) offers a compelling strategy to enhance phage antibiofilm efficacy.