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

Estelle J Ramchuran,Nikhil Agrawal,Shimaa A H Abdel Monaim,Daniel G Amoako,Raveen Parboosing,Beatriz G De La Torre,Linda A Bester,Hezekiel M Kumalo,Anou M Somboro,Fernando Albericio

doi:10.3389/fmicb.2018.01535

Estelle J Ramchuran, Nikhil Agrawal + Show 8 more

Open Access

https://doi.org/10.3389/fmicb.2018.01535

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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.

Highlights

The rate of antibiotic resistance is increasing faster than the development of new compounds for clinical practice
As Lallo-End was not commercially available, our group concentrated their efforts on synthesizing Arg10-Teixobactin (2, Figure 1), in which the L-allo-End is substituted by Arg (Jad et al, 2015; Parmar et al, 2016)
Antibiotic resistance in Gram-positive bacteria is increasing worldwide, as indicated by the WHO list of highpriority pathogens (i.e., vancomycin-resistant enterococcus (VRE) and Methicillin-resistant Staphylococcus aureus (MRSA)), much attention has shifted to combating Gram-negative bacteria

Summary

Introduction

The rate of antibiotic resistance is increasing faster than the development of new compounds for clinical practice. In an extremely short period, resistance to antibiotics has become a significant cause of disease and death globally (Penesyan et al, 2015; Brown and Wright, 2016; Hamilton and Wenlock, 2016). Limited success in collective research efforts to synthesize novel and efficient compounds has contributed to the drug-resistance scenario we are facing and to the lack of new and efficient treatment options. The first antibiotics were produced through screening soil microorganisms. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria, which make up 99% of all species in external environments, emerge as a potent source of new antibiotics (Kaeberlein et al, 2002; Nichols et al, 2010; Fang et al, 2012)

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