The Triprenylated Anthranoid Ferruginin A, a Promising Scaffold for the Development of Novel Antibiotics against Gram-Positive Bacteria.

Bruno Casciaro,Floriana Cappiello,Maria Rosa Loffredo,Bruno Botta,Deborah Quaglio,Elena Puglisi,Mattia Mori,Valeria Vergine,Francesca Ghirga,Maria Luisa Mangoni,Silvia Cammarone,Carola Tortora

doi:10.3390/antibiotics11010084

Bruno Casciaro, Floriana Cappiello + Show 10 more

Open Access

https://doi.org/10.3390/antibiotics11010084

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Abstract

In today’s post-antibiotic era, the search for new antimicrobial compounds is of major importance and nature represents one of the primary sources of bioactive molecules. In this work, through a cheminformatics approach, we clustered an in-house library of natural products and their derivatives based on a combination of fingerprints and substructure search. We identified the prenylated emodine-type anthranoid ferruginin A as a novel antimicrobial compound. We tested its ability to inhibit and kill a panel of Gram-positive and Gram-negative bacteria, and compared its activity with that of two analogues, vismione B and ferruanthrone. Furthermore, the capability of these three anthranoids to disrupt staphylococcal biofilm was investigated, as well as their effect on the viability of human keratinocytes. Ferruginin A showed a potent activity against both the planktonic and biofilm forms of Gram-positive bacteria (i.e., Staphylococcus aureus and S. epidermidis) and had the best therapeutic index compared to vismione B and ferruanthrone. In conclusion, ferruginin A represents a promising scaffold for the further development of valuable antimicrobial agents.

Highlights

The discovery of penicillin and the subsequent use of antibiotics in the treatment of bacterial infections has drastically changed human lifespan, increasing it by about 23 years [1].the golden age of antibiotics is at the end; fewer and fewer compounds are being developed, while the onset of multidrug-resistant strains is increasing, making classic therapies mostly useless [2]
Our in-house library is a valid source of chemotypes for the modulation of biomolecular targets, and it has been successfully screened in silico and in vitro for the identification of hit and lead compounds in previous early-stage drug discovery projects [7]
A diversity-oriented random selection (DORS) of compounds was performed by means of a clustering algorithm, which relies on a combination of fingerprints and common substructure search to group compounds endowed with chemical similarity index within a given threshold [14]

Summary

Introduction

The golden age of antibiotics is at the end; fewer and fewer compounds are being developed, while the onset of multidrug-resistant strains is increasing, making classic therapies mostly useless [2]. It is difficult to quantify and to predict the number of deaths per year due to AMR, it is estimated that in 2050 it will be 10 million [3]. These numbers are alarming, considering that many microorganisms can transition from a planktonic lifestyle to a sessile form, called biofilm. Bacterial cells are surrounded by extra-cellular polymeric substances and DNA, which protect them from the antibiotic action, making their eradication even more difficult [4]

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