Phage steering of antibiotic-resistance evolution in the bacterial pathogen, Pseudomonas aeruginosa

Abstract

Our study supports a trade-off between antibiotic resistance and phage sensitivity. This trade-off was maintained over co-evolutionary time scales even under combined phage and antibiotic pressure. Similarly, OMKO1 maintained this trade-off <i>in vivo,</i> again under dual phage/antibiotic pressure. Our findings have implications for the future clinical use of steering in phage therapies. <b>Lay Summary:</b> Given the rise of antibiotic-resistant bacterial infection, new approaches to treatment are urgently needed. Bacteriophages (phages) are bacterial viruses. The use of such viruses to treat infections has been in near-continuous use in several countries since the early 1900s. Recent developments have shown that these viruses are not only effective against routine infections but can also target antibiotic resistant bacteria in a novel, unexpected way. Similar to other lytic phages, these so-called 'steering phages' kill the majority of bacteria directly. However, steering phages also leave behind bacterial variants that resist the phages, but are now sensitive to antibiotics. Treatment combinations of these phages and antibiotics can now be used to greater effect than either one independently. We evaluated the impact of steering using phage OMKO1 and a panel of three antibiotics on <i>Pseudomonas aeruginosa</i>, an important pathogen in hospital settings and in people with cystic fibrosis. Our findings indicate that OMKO1, either alone or in combination with antibiotics, maintains antibiotic sensitivity both <i>in vitro</i> and <i>in vivo</i>, giving hope that phage steering will be an effective treatment option against antibiotic-resistant bacteria.