Abstract
The rapid emergence of multidrug-resistant pathogens has evolved into a global health problem as current treatment options are failing for infections caused by pan-resistant bacteria. Hence, novel antibiotics are in high demand, and for this reason antimicrobial peptides (AMPs) have attracted considerable interest, since they often show broad-spectrum activity, fast killing and high cell selectivity. However, the therapeutic potential of natural AMPs is limited by their short plasma half-life. Antimicrobial peptidomimetics mimic the structure and biological activity of AMPs, but display extended stability in the presence of biological matrices. In the present review, focus is on the developments reported in the last decade with respect to their design, synthesis, antimicrobial activity, cytotoxic side effects as well as their potential applications as anti-infective agents. Specifically, only peptidomimetics with a modular structure of residues connected via amide linkages will be discussed. These comprise the classes of α-peptoids (N-alkylated glycine oligomers), β-peptoids (N-alkylated β-alanine oligomers), β3-peptides, α/β3-peptides, α-peptide/β-peptoid hybrids, α/γ N-acylated N-aminoethylpeptides (AApeptides), and oligoacyllysines (OAKs). Such peptidomimetics are of particular interest due to their potent antimicrobial activity, versatile design, and convenient optimization via assembly by standard solid-phase procedures.
Highlights
Antimicrobial resistance (AMR) is a global health-care problem causing the death of nearly 700,000 people each year [1], and predictions indicate that this number may reach up to 10 million deaths annually by 2050
Recent advances in development of antimicrobial peptidomimetics as potential drugs have been discussed with respect to accessibility via chemical synthesis and optimization strategies for obtaining compounds with an appropriate pharmacological profile
The key hurdles with peptidomimetics as therapeutics are: (i) availability; (ii) toxicity; (iii) bioavailability; and (iv) drug approval regulations
Summary
Antimicrobial resistance (AMR) is a global health-care problem causing the death of nearly 700,000 people each year [1], and predictions indicate that this number may reach up to 10 million deaths annually by 2050. According to the Infectious Diseases Society of America (IDSA), the most worrying bacteria comprise the multidrug-resistant (MDR) ESKAPE pathogens Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Enterobacter species, which together cause the majority of US hospital infections. Resistance to the last-resort antibiotics colistin and carbapenems for treatment of difficult Gram-negative infections is spreading rapidly. Multidrug resistance in Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Clostridium difficile remains a challenge in infectious diseases. Pet animals are often treated with the same types of antibiotics as humans, thereby enhancing the risk of AMR development in humans [13]. Infections caused by MRSP (the main reason for antibiotic prescription in dogs) are challenging to eradicate, but MRSP is still considered a rare pathogen in humans, albeit with an increasing number of cases reported each year [16]. A number of recent regulatory incentives for antibiotic drug development have been proposed as reviewed by Sinha [20]
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