Interactions and mechanisms of bacteriophages and antibiotics in phage cocktails

Summary: Dr Nicholls is an Assistant Professor in the Section of Infectious Diseases at Baylor College of Medicine (BCM) and a basic science researcher in the field of phage biology for antibiotic resistant infections. His career goals are to integrate high quality basic science research with clinical practice to treat patients with resistant bacterial infections. Drug resistant Pseudomonas has become common and is a global priority for the WHO and CDC. It affects a broad spectrum of people from children with ventricular assist devices to adults with chronic osteomyelitis. Unfortunately, new antibiotic development has not kept pace with bacterial evolution, but bacteriophages that can infect these bacteria offer a possible solution. Dr Nicholls’ goal is to become a leader in the science underlying the phage therapy for these challenging cases. To accomplish this, he has prepared comprehensive research and career development plans to integrate his clinical practice and basic science research goals. Dr Nicholls’ career development will be guided by regular meetings with his primary mentor, Dr Anthony Maresso. Dr Maresso is a leader in the field of bacteriophage biology and founder of the BCM affiliate TAILΦR Labs, specialising in phages for the treatment of resistant infections. Further guidance to develop an independent career in will be gathered from biophysicist Dr Andres Oberhauser. Clinical expertise will be brought to his development by Dr Saima Aslam, a clinician and prominent phage researcher. His research and career development will be supported by the laboratory facilities of Dr Maresso and the world class collaborative scientific environment of BCM. Dr Nicholls’ research is divided into 2 specific aims. The first aim is to characterise phage-antibiotic and phage- phage interactions to maximise planktonic and biofilm killing as well as biomechanical degradation of biofilms. The second aim to identify phages to selectively reduce the fitness of bacterial survivors and study evolutionary pathways to recover fitness. These aims are severable in that none depends on the success of the others. However, they all work together to guide the rational design of phage cocktails to maximise the yield of interactions and select bacterial successors with weaker phenotypes. This proposal will directly guide phage cocktail development for more effective therapeutics. The proposal is designed to provide a broad experience in phage biology as well as career development activities to allow Dr Nicholls to make the difficult transition to independence as a clinician scientist and expert in phage treatment of resistant infections.