Therapeutic potential of mycobacteriophage LysB against Mycobacterium abscessus infections

Summary M. abscessus (Mab) infections are life-threatening to people with certain underlying health conditions. A combination of an oral macrolide and the aminoglycoside, amikacin, comprises the frontline treatment against Mab and is used in conjunction with one or more of the injectable drugs- cefoxitin, imipenem or tigecycline- for a period of 6-12 months. Despite these intensive interventions, cure rates are low (~30-50%), which is largely attributed to the intrinsic resistance of Mab to most of the clinically approved drugs. There is an urgent need for new therapeutics for the treatment of Mab infections. While natural and engineered mycobacteriophages have shown promise in the treatment of Mab infections in several compassionate use cases, their narrow host preference combined with extensive Mab strain diversity present challenges to the broader implementation of the phage therapy. In a recent study, we demonstrated therapeutic potential of a D29 mycobacteriophage lysin, LysB, against Mab infection in an acute mouse model. A 6-day intrapulmonary treatment of Mab-infected mice with aerosolized D29-LysB reduced the bacterial burden by 20-fold. Moreover, in contrast to the phages, which preferentially target rough-colony variants of Mab, D29-LysB is equally efficient in killing both rough- and smooth-colony variants of Mab in vitro. These pre-clinical findings together reveal LysB as a broad-spectrum therapeutic adjunct for achieving rapid clearance of Mab infection, particularly in the lung airways. In this project we will develop the therapeutic potential of LysB and test the hypothesis that a combination therapy of aerosolized LysB and amikacin will shorten the treatment of Mab infections. First, we will generate a cocktail of complementary LysB enzymes to target a diverse set of Mab strains. Second, we will decipher the mechanism of Mab lysis by LysB. Third, we will evaluate LysB-antibiotic synergy against Mab in acute and chronic mouse infection models. Development of LysB as a novel therapeutic against Mab infection will offer new approaches to increase the treatment efficacy while reducing the duration and dosage of drug exposure.