New Antimicrobials Based on the Adarotene Scaffold with Activity against Multi-Drug Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococcus.

Salvatore Princiotto,Claudio Pisano,Stefania Mazzini,Loana Musso,Fabio Arena,Sabrina Dallavalle

doi:10.3390/antibiotics10020126

Salvatore Princiotto, Claudio Pisano + Show 4 more

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https://doi.org/10.3390/antibiotics10020126

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Abstract

The global increase in infections by multi-drug resistant (MDR) pathogens is severely impacting our ability to successfully treat common infections. Herein, we report the antibacterial activity against S. aureus and E. faecalis (including some MDR strains) of a panel of adarotene-related synthetic retinoids. In many cases, these compounds showed, together with favorable MICs, a detectable bactericidal effect. We found that the pattern of substitution on adarotene could be modulated to obtain selectivity for antibacterial over the known anticancer activity of these compounds. NMR experiments allowed us to define the interaction between adarotene and a model of microorganism membrane. Biological assessment confirmed that the scaffold of adarotene is promising for further developments of non-toxic antimicrobials active on MDR strains.

Highlights

Bacterial resistance to antimicrobial drugs is becoming one of the major threats to human health
It has been recently found that CD-437 related synthetic retinoids exhibit antimicrobial activity on methicillin-resistant S. aureus (MRSA)
Having in our hands a large number of retinoids containing the adarotene scaffold, we tested some representative derivatives as antimicrobial agents to have an insight of the most relevant structural features affecting the activity

Summary

Introduction

Bacterial resistance to antimicrobial drugs is becoming one of the major threats to human health. Though there are no extensive data that globally define the phenomenon of antimicrobial resistance (AMR), the latest estimates show that it is the cause of over 700,000 deaths per year worldwide [4,5]. Compound 2, with an OH-ending alkyl chain linked to the phenolic group was the worst analogue of the series, with a MIC > 256 μg/mL for both S. aureus and E. faecalis strains. The introduction of a lipid-mimicking unsaturated alkyl chain (compound 3) caused an increase in MICs (32 μg/mL for S. aureus, 128 μg/mL for E. faecalis), confirming that the phenolic hydroxy group plays an essential role for activity. Compounds 7, 8, 9 had a MIC 2–4 μg/mL for S. aureus and 1–4 μg/mL for E. faecalis and a bactericidal activity in all except one case

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