In Vitro Antibacterial Activity of Teixobactin Derivatives on Clinically Relevant Bacterial Isolates

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE) are included on the WHO high priority list of pathogens that require urgent intervention. Hence emphasis needs to be placed on developing novel class of molecules to tackle these pathogens. Teixobactin is a new class of antibiotic that has demonstrated antimicrobial activity against common bacteria. Here we examined the antimicrobial properties of three Teixobactin derivatives against clinically relevant bacterial isolates taken from South African patients. The minimum inhibitory concentration (MIC), the minimal bactericidal concentration (MBC), the effect of serum on MICs and the time-kill kinetics studies of our synthesized Teixobactin derivatives (3, 4, and 5) were ascertained following the CLSI 2017 guidelines and using the broth microdilution method. Haemolysis on red blood cells (RBCs) and cytotoxicity on peripheral blood mononuclear cells (PBMCs) were performed to determine the safety of these compounds. The MICs of 3, 4, and 5 against reference strains were 4–64 μg/ml, 2–64 μg/ml, and 0.5–64 μg/ml, respectively. The MICs observed for MRSA were (3) 32 μg/ml, (4) 2–4 μg/ml and (5) 2–4 μg/ml whilst those for VRE were (3) 8–16 μg/ml, (4) 4 μg/ml and (5) 2–16 μg/ml, respectively. In the presence of 50% human serum, there was no significant effect on the MICs. The compounds did not exhibit any effect on cell viability at their effective concentrations. Teixobactin derivatives (3, 4, and 5) inhibited bacterial growth in drug-resistant bacteria and hence emerge as potential antimicrobial agents. Molecular dynamic simulations suggested that the most dominant binding mode of Lys10-teixobactin (4) to lipid II is through the amide protons of the cycle, which is identical to data described in the literature for the natural teixobactin hence predicting the possibility of a similar mechanism of action.

Enhancing the antibacterial activity of PMAP‐37 by increasing its hydrophobicity

“…The hemolytic effects of PMAP‐37 and its analogs were investigated as described previously (Oddo & Hansen, ; Ramchuran et al, ). An 8% suspension of mouse erythrocytes was prepared with PBS, and 100 μl was added to a 96‐well plate containing PMAP‐37 or PMAP‐37 analogs at different concentrations.…”

Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

“…Both sensitive Gram-positive MRSA and VRE isolates were inhibited, to a superior level than that of vancomycin [213]. The strong bactericidal activity may be accredited to the synergistic inhibition of the synthesis of both peptidoglycan and cell wall teichoic acid [213].…”

“…Another in vitro study that evaluated three synthesised derivatives of teixobactin to determine their activity against both Gram-positive and Gram-negative bacteria also demonstrated potent antimicrobial activity against Gram-positive bacteria [213]. Both sensitive Gram-positive MRSA and VRE isolates were inhibited, to a superior level than that of vancomycin [213]. The strong bactericidal activity may be accredited to the synergistic inhibition of the synthesis of both peptidoglycan and cell wall teichoic acid [213].…”

Dissecting the Binding Interactions of Teixobactin with the Bacterial Cell‐Wall Precursor Lipid II

“…Interest in the peptide's activity and therapeutic potential led to curiosity in synthetic approaches to access teixobactin; with two distinct synthetic routes reported just a year later . Following the initial report, several studies were aimed at understanding the spectrum of antimicrobial activity, structure–activity studies, interrogating the mode of action through modelling, and structural investigations . These studies yielded insight into key residues, modifiable regions, and suspected binding sites of teixobactin to its cellular targets—the bacterial cell wall precursors: lipid II (Figure B) and lipid III.…”