Increasing rates of antibiotic resistance, coupled with a lack of new antibiotics for ‘difficult to treat’ pathogens, has resulted in an urgent need for alternative approaches to antibiotic development. This is particularly true for Gram-negative pathogens, such as P. aeruginosa and Enterobacteriaceae, which, due to intrinsic, acquired and adaptive resistance mechanisms, are now the leading cause of hospital-acquired infections. This is exemplified in cystic fibrosis patients where, despite aggressive antibiotic therapy, chronic lung infection with P. aeruginosa, coupled with the concomitant intense inflammatory response and progressive loss of lung function, is the major cause of morbidity and mortality in this patient group.
An alternative strategy for antibiotic development is to utilise S-type pyocins. These are highly specific and extremely potent protein antibiotics (bacteriocins) used by P. aeruginosa for intraspecies competition.
This work demonstrates the potential for the therapeutic application of pyocins. The exceptional potency of pyocins, previously demonstrated in vitro, translated well to a murine model of acute P. aeruginosa lung infection (as measured by a reduction in colony forming units) for a range of clinical and environmental isolates. Additionally, the concentration of pyocin required to afford protection from a lethal P. aeruginosa infection was at least 100-fold lower than tobramycin, the most widely used antibiotic against this pathogen. Importantly for a protein therapeutic there was no evidence of inflammation or damage to lung tissue after a single administration of pyocin and the repeated administration of pyocin, 5-log units in excess of its effective therapeutic dose, caused only mild and focal inflammation in the lung.
This is the first study investigating the use of bacteriocins from Gram-negative bacteria as therapeutics in a murine model. Bacteriocin encoding genes are frequently found in microbial genomes and could offer a ready supply of potent antibiotics specifically targeted against problematic Gram-negative bacterial pathogens.