Unnatural amino acids: promising implications for the development of new antimicrobial peptides

The increasing incidence and rapid spread of bacterial resistance to conventional antibiotics are a serious global threat to public health, highlighting the need to develop new antimicrobial alternatives. Antimicrobial peptides (AMPs) represent a class of promising natural antibiotic candidates due to their broad-spectrum activity and low tendency to induce resistance. However, the development of AMPs for medical use is hampered by several obstacles, such as moderate activity, lability to proteolytic degradation, and low bioavailability. To date, many researchers have focussed on the optimization or design of novel artificial AMPs with desired properties. Unnatural amino acids (UAAs) are valuable building blocks in the manufacture of a variety of pharmaceuticals, and have been used to develop artificial AMPs with specific structural and physicochemical properties. Rational incorporation of UAAs has become a very promising approach to endow AMPs with strong and long-lasting activity but no toxicity. This review aims to summarize key approaches that have been used to incorporate UAAs to develop novel AMPs with improved properties and better performance. It is anticipated that this review will guide future design considerations for UAA-based antimicrobial applications.