Advances in the development of antimicrobial peptides and proteins for inhaled therapy

Antimicrobial peptides and proteins (APPs) are becoming increasingly important in targeting multidrugresistant (MDR) bacteria. APPs is a rapidly emerging area with novel molecules being produced and further optimised to enhance antimicrobial efficacy, while overcoming issues associated with biologics such as potential toxicity and low bioavailability resulting from short half-life. Inhalation delivery of these agents can be an effective treatment of respiratory infections owing to the high local drug concentration in the lungs with lower exposure to systemic circulation hence reducing systemic toxicity. This review describes the recent studies on inhaled APPs, including in vitro and in vivo antimicrobial activities, toxicity assessments, and formulation strategies whenever available. The review also includes studies on combination of APPs with other antimicrobial agents to achieve enhanced synergistic antimicrobial effect. Since different APPs have different biological and chemical stabilities, a targeted formulation strategy should be considered for developing stable and inhalable antimicrobial peptides and proteins. These strategies include the use of sodium chloride to reduce electrostatic interaction between APP and extra cellular DNA in sputum, the use of D-enantiomers or dendrimers to minimise protease-mediated degradation and or the use of prodrugs to reduce toxicity. Although great effort has been put towards optimising the biological functions of APPs, studies assessing biological stability in inhalable aerosols are scarce, particularly for novel molecules. As such, formulation and manufacture of inhalable liquid and powder formulations of APPs are underexplored, yet they are crucial areas of research for clinical translation.(c) 2021 Elsevier B.V. All rights reserved.

Automated summary

Antimicrobial peptides and proteins play an increasingly important role in treating multidrug-resistant bacterial infections. Inhalation delivery of these agents can effectively increase local drug concentration in the lungs and reduce systemic toxicity. Targeted formulation strategies are needed to improve stability and inhalability of different antimicrobial peptides and proteins, as well as their combination with other antimicrobial agents. However, research on inhalable formulations of these agents is still underexplored, which is a crucial area for clinical translation.