Nitric oxide pretreatment enhances ofloxacin susceptibility of biofilm concomitant with exopolysaccharide depletion

Abstract When faced with the dilemma that the safe, cheap, and plentiful antibiotics failed in fighting obstinate biofilm, progress has been made to use low-dose nitric oxide (NO) as adjunctive therapy for enhancing antibiotic efficacy. To further potentiate antibiotic against biofilm, we investigated the sequential role of NO and ofloxacin to treat Pseudomonas aeruginosa biofilm. Here we showed that the pretreatment of NO rendered antibiotics to eradicate recalcitrant biofilm, increasing ofloxacin efficacy up to 3 orders of magnitude. It proceeded by reducing exopolysaccharides within biofilm which facilitated biofilm dispersal. Additionally, we verified that the pretreatment of NO could improve the therapeutic efficacy of antibiotics in vivo by a chronic lung infection model. We believe that the strategy will provide a powerful demonstration of biofilm eradication, highlighting the sequential delivery of NO and bactericides to combat chronic bacterial infection.