Tridecaptin-inspired antimicrobial peptides with activity against multidrug-resistant Gram-negative bacteria

Abstract

New tridecaptin analogues are cheaper to make and retain strong Gram-negative activity.

A Chemical-Intervention Strategy To Circumvent Peptide Hydrolysis by d-Stereoselective Peptidases

“…Linear analogues 3 – 8 were previously synthesized, where d - and l -Dab residues were replaced with d - and l -Orn/Lys, respectively, to test if conservative substitutions with cheaper amino acids can make tridecaptin synthesis more cost efficient. 20 To determine if any of these modifications were able to impart resistance to BogQ, tridecaptin analogues 1 – 11 were incubated with this d -peptidase and analyzed by ultraperformance liquid chromatography coupled mass spectrometry (UPLC–MS). We were surprised to find that all analogues are rapidly hydrolyzed by BogQ at the 2 and 8 positions (all >90% after 1 h).…”

“…Although this peptide is 2- to 4-fold less active than Oct-TriA 1 ( 1 ) ( d - a Ile12), it is significantly cheaper to synthesize. 20 The susceptibility of these peptides to BogQ and TriF and their antimicrobial activity against a model Gram-negative ( Escherichia coli NCTC 12241) and Gram-positive ( Staphylococcus aureus NCTC 10788) organism were tested (Table 1, Figure 2). Peptides were synthesized from Ala-2-chlorotrityl resin (0.8 mmol/g) using manual or automated (CEM Liberty 12 peptide synthesizer) Fmoc solid-phase peptide synthesis (SPPS).…”

“…A previous tridecaptin SAR study found that having d - allo -Ile at the 12 position (as in Oct-TriA 1 ) provides a 2- to 4-fold increase in antimicrobial activity. 20 Therefore, Oct-TriA 1 analogues 24 and 25 , which incorporate some of these modifications, were synthesized and tested. As expected, peptides 24 and 25 have total TriF resistance and substantially improved BogQ resistance; however substitution of d -Val12 with d - a Ile had minimal effect on antimicrobial activity.…”

Development and Challenges of Antimicrobial Peptides for Therapeutic Applications

“…Numerous approaches to peptide design have been introduced to make AMPs less toxic for humans while maintaining or improving their potency to eliminate bacteria [11,42], e.g., rational design [119,120], combinatorial peptide libraries [75,121], high-throughput screening [122,123], database-guided approaches [124,125], structure-function-guided design [86,126,127], and molecular dynamics simulations [44]. Three major methods to improve AMP function have been described: (i) High-throughput screening can be used to identify potential AMPs [128][129][130].…”

Turning a Collagenesis-Inducing Peptide Into a Potent Antibacterial and Antibiofilm Agent Against Multidrug-Resistant Gram-Negative Bacteria

“…As efficient options to fight MDR bacteria are being exhausted, preclinical and clinical development of antimicrobial peptides (AMPs) has been experiencing a strong impulse (Aminov, 2010; Gomes et al, 2017; Costa et al, 2019). AMPs have broad-spectrum antibacterial activity, and low propensity to induce resistance, hence latest efforts in this area have been focused on the search for AMPs with potent action, particularly against MDR Gram-negative bacteria (Ballantine et al, 2019; Mant et al, 2019; Wang et al, 2019). Findings thereof are quite encouraging toward devising new options to tackle cSSTI like DFU, as the most prevalent bacterial species isolated from these ulcers include, besides the Gram-positive S. aureus , several Gram-negative species like P. aeruginosa , E. coli , K. pneumonia , and Proteus mirabilis (Ogba et al, 2019).…”