Although antibiotic-resistant invasive pneumococcal infections have decreased since the introduction of polysaccharide conjugate vaccines, more than 2 million pneumococcal infections occur every year only in the United States, with more than 30% resistant cases to one or more clinically relevant antibiotics, resulting in more than 6000 deaths and USD 4 billion in total costs. It is a major causative agent of pneumonia, meningitis, sepsis, and otitis media, with 1 million deaths estimated per year, and it is the leading organism in terms of years of life lost (YLL), with 40.3 million YLL.

One of the major pathogens worldwide affected by AMR issues is Streptococcus pneumoniae (pneumococcus). These results open new possibilities to tackle pneumococcal disease through drug repositioning and provide clues for the design of novel membrane-targeted antimicrobials with a related chemical structure. Moreover, all compounds but mitoxantrone caused a remarkable increase in the permeability of the bacterial membrane and share a common, minimal chemical structure consisting of an aliphatic amine linked to a phenyl moiety via a short carbon/oxygen linker. These molecules arrested pneumococcal growth in a liquid medium and induced a decrease in bacterial viability between 90.0% and 99.9% at 25 µM concentration, with minimal inhibitory concentrations (MICs) also in the micromolar range. After four discrimination rounds, a set of seven compounds was finally selected, namely (i) clofilium tosylate (ii) vanoxerine (iii) mitoxantrone dihydrochloride (iv) amiodarone hydrochloride (v) tamoxifen citrate (vi) terfenadine and (vii) clomiphene citrate (Z, E).

A collection of repurposing drugs (Prestwick Chemical Library) containing 1200 compounds was screened to investigate the drugs’ antimicrobial effects against planktonic cultures of the respiratory pathogen Streptococcus pneumoniae.

Z library free