Rational design of inhaled antibacterials targeting alveolar macrophages for efficient killing of resistant bacteria associated with lower respiratory tract infections (LRTIs)

Lower respiratory tract infections (LRTIs), caused by antibiotic-resistant bacteria, are a leading cause of global death and morbidity. One of the principal limitations in treating respiratory bacterial infections is inefficient delivery and appropriate therapeutic drug concentrations to infected cells, as required to kill resistant bacteria. Inhaled antibiotic delivery technology specifically delivers antibacterials directly into the infected cells of the lungs and provides the required therapeutic concentration at a very low delivered dose, with a greatly reduced risk of systemic adverse effects. An alveolar macrophage (AM)-targeted antibiotic delivery strategy utilizing receptor-ligand interactions or stimuli-responsive mechanisms of drug release demonstrated efficient killing of intracellular bacteria. The rational design of antibacterials or formulations for inhalation is the key to achieving this goal. Based on ligand chemistry, decorating antibiotic carriers with ligands that target specific AM receptors is a novel strategy to ensure precise antibiotic delivery to the site of infection while reducing both the side effects associated with high systemic doses and the risk of further promoting antibiotic resistance. This review highlights advances in AM-targeted inhaled antibacterials, identification of appropriate ligands for specific AM receptors, mechanisms of interaction, and subsequent release of antibiotics through carrier degradation, pH-responsive behavior, or enzymatic cleavage to eradicate resistant bacteria. Finally, we discuss the ongoing challenges and future directions for AM-targeted inhaled antibacterials against LRTIs.