Indole-containing arene-ruthenium complexes with broad spectrum activity against antibiotic-resistant bacteria.

Maria Azmanova,Colin C. Seaton,Marialuisa Crosatti,Malgorzata Wegrzyn,Danielle L. Timms,Laia Rafols,Joan J. Soldevila-Barreda,James Harrison,Natalie J. Garton,Helen Sendron,Victoria C. Nolan,Jonathan A.G. Cox,Anaïs Pitto-Barry,Nicolas P.E. Barry

doi:10.1016/j.crmicr.2021.100099

Abstract

Antimicrobial resistant (AMR) bacteria are emerging and spreading globally, threatening our ability to treat common infectious diseases. The development of new classes of antibiotics able to kill or inhibit the growth of such AMR bacteria through novel mechanisms of action is therefore urgently needed. Here, a new family of indole-containing arene ruthenium organometallic compounds are screened against several bacterial species and drug resistant strains. The most active complex [(p-cym)Ru(O-cyclohexyl-1H-indole-2-carbothioate)Cl] (3) shows growth inhibition and bactericidal activity against different organisms (Acinetobacter baumannii, Mycobacterium abscessus, Mycobacterium tuberculosis, Staphylococcus aureus, Salmonella enterica serovar Typhi and Escherichia coli), demonstrating broad-spectrum inhibitory activity. Importantly, this compound series exhibits low toxicity against human cells. Owing to the novelty of the antibiotic family, their moderate cytotoxicity, and their inhibitory activity against Gram positive, Gram negative and acid-fast, antibiotic resistant microorganisms, this series shows significant promise for further development.

Highlights

Antibiotic resistance is a worldwide threat to public health, food security, and economic and societal developments.[1]
We have recently developed an interest in investigating the effect of bio-active indole moieties as bidentate ligands on the biological properties of half-sandwich metal complexes.[35]
The indole 2-carboxylate ligands L2 – L5 were synthesised by esterification of 1H-indole-2-carboxylic acid (L1) with the corresponding alcohol (MeOH, EtOH, CyOH, PhOH, respectively)

Summary

Introduction

Antibiotic resistance is a worldwide threat to public health, food security, and economic and societal developments.[1] The prevalence of antimicrobial resistance (AMR) among common pathogens is rapidly increasing, which leads to widespread diseases becoming harder, or impossible, to cure. Several other multidrug-resistant Gram-negative organisms.[2] In the last decades, a global effort has allowed the development of new antibiotic drugs with activity against common AMR organisms,[3] but resistance against such agents is already emerging. There is an urgent need to find new families of compounds with high levels of antibacterial activity, novel mechanisms of action and low frequencies of antibiotic resistance. Medicinal inorganic chemistry has been stimulated by the success of platinum anticancer drugs (used as a component of nearly 50% of all cancer chemotherapy treatments), by the use of gadolinium(III) complexes as MRI contrast agents (about 20 million doses administered per year), and of the radionuclide 99m-technetium radiopharmaceuticals for γ-ray imaging (used in about 20 million radio diagnostic procedures each year).[7,8,9,10] the involvement of metals in many other diseases and conditions is of current interest in relation to their causes, their treatment or detection, including neurodegeneration,[11]

Methods

Results

Conclusion