Peptide Targeting of an Antibiotic Prodrug toward Phagosome-Entrapped Mycobacteria.
Mycobacterial infections are difficult to treat due to the bacterium's slow growth, ability to reside in intracellular compartments within macrophages, and resistance mechanisms that limit the effectiveness of conventional antibiotics. Developing antibiotics that overcome these challenges is therefore critical to providing a pipeline of effective antimicrobial agents. Here, we describe the synthesis and testing of a unique peptide-drug conjugate that exhibits high levels of antimicrobial activity against M. smegmatis and M. tuberculosis as well as clearance of intracellular mycobacteria from cultured macrophages. Using an engineered peptide sequence, we deliver a potent DHFR inhibitor and target the intracellular phagosomes where mycobacteria reside and also incorporate a β-lactamase-cleavable cephalosporin linker to enhance the targeting of quiescent intracellular β-lactam-resistant mycobacteria. By using this type of prodrug approach to target intracellular mycobacterial infections, the emergence of antibacterial resistance mechanisms could be minimized.
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, and Department of Biochemistry, Faculty of Medicine, University of Toronto , Toronto, Ontario, Canada.
Mark P
MP
Pereira
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, and Department of Biochemistry, Faculty of Medicine, University of Toronto , Toronto, Ontario, Canada.
Julie
J
Shi
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, and Department of Biochemistry, Faculty of Medicine, University of Toronto , Toronto, Ontario, Canada.
Shana O
SO
Kelley
Mycobacterium tuberculosis; cephalosporin; methotrexate; peptide; prodrug; β-lactamase