Abstract
We designed de novo and synthesized two series of five 26-residue amphipathic α-helical cationic antimicrobial peptides (AMPs) with five or six positively charged residues (D-Lys, L-Dab (2,4-diaminobutyric acid) or L-Dap (2,3-diaminopropionic acid)) on the polar face where all other residues are in the D-conformation. Hemolytic activity against human red blood cells was determined using the most stringent conditions for the hemolysis assay, 18h at 37°C, 1% human erythrocytes and peptide concentrations up to 1000 μg/mL (~380 μM). Antimicrobial activity was determined against 7 Acinetobacter baumannii strains, resistant to polymyxin B and colistin (antibiotics of last resort) to show the effect of positively charged residues in two different locations on the polar face (positions 3, 7, 11, 18, 22 and 26 versus positions 3, 7, 14, 15, 22 and 26). All 10 peptides had two D-Lys residues in the center of the non-polar face as “specificity determinants” at positions 13 and 16 which provide specificity for prokaryotic cells over eukaryotic cells. Specificity determinants also maintain excellent antimicrobial activity in the presence of human sera. This study shows that the location and type of positively charged residue (Dab and Dap) on the polar face are critical to obtain the best therapeutic indices.
Highlights
The growing emergence of pathogenic bacteria with clinically significant resistance to conventional antibiotics is a major public health concern [1,2,3,4,5]
While the 2016 review [4] offered a plethora of approaches to slowing down or preventing future bacterial resistance to antibiotics, the fact remains that organisms resistant to conventional antibiotics will still be present and must be dealt with
It has frequently been asserted that, as part of a global response to MDR bacteria, we must increase the number of effective antimicrobial drugs to defeat infections that have become resistant to existing antibiotics [4]
Summary
The growing emergence of pathogenic bacteria with clinically significant resistance to conventional antibiotics is a major public health concern [1,2,3,4,5]. The scope of the challenge in tackling drug-resistant infections globally is reported in detail in a 2016 review on antimicrobial resistance [4]. It has frequently been asserted that, as part of a global response to MDR bacteria, we must increase the number of effective antimicrobial drugs to defeat infections that have become resistant to existing antibiotics [4]. Between 1929 and the 1970s, more than 20 new classes (not just analogs of an existing class) of antibiotic reached the market [3]. Only two new classes have reached the market, with the worldwide antibiotic pipeline for Journal of Medicinal Chemistry and Drug Design Open Access Journal new antibiotic classes active against highly resistant Gram-negative bacteria being almost non-existent [3]. The fundamental problem with this approach is that, analog development is low risk compared to novel class discovery and development, analogs eventually became more difficult to come by and the process hits a dead end
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