Exploring phage early genes to combat drug-resistant Acinetobacter baumannii

Acinetobacter baumannii is a critically important multidrug-resistant pathogen associated with severe hospital-acquired infections. Bacteriophages have emerged as a promising alternative; however, the mechanisms underlying phage-host interactions remain poorly understood. Early phage genes, expressed shortly after infection, play a crucial role by hijacking the host’s cellular machinery to prioritise phage replication. Notably, some of these early genes can independently inhibit bacterial growth, highlighting their potential as novel therapeutic agents. In this study, we explored the interaction between two phages – a podovirus-like and a siphovirus-like phage – and their drug-resistant A. baumannii hosts, using transcriptomic approaches, such as RNA-seq. We have identified both phages’ early genes, selected those with unknown function and individually evaluated their ability to inhibit bacterial growth. Among them, one gene of each phage exhibited a strong inhibitory effect, reducing CFU/mL counts by up to 4 logs. Additionally, although these phages can only infect their host’s specific capsular type, we confirmed that these genes are effective across different A. baumannii strains, while remaining non-toxic to commensal species, such as E. coli. Further ongoing studies are focused on understanding if these genes can act synergistically. Furthermore, uncovering the mechanisms by which phages infect their hosts is essential, not only for the development of phage-derived therapeutics but also to find essential bacterial pathways that may serve as targets. Thus, elucidating the mechanism of inhibition is equally important. Ongoing studies are focused on identifying the bacterial interaction partner of the inhibitory genes.