Novel Iron-Chelator DIBI Inhibits Staphylococcus aureus Growth, Suppresses Experimental MRSA Infection in Mice and Enhances the Activities of Diverse Antibiotics in vitro.

Maria Del Carmen Parquet,Bruce E Holbein,Ross J Davidson,David S Allan,Kimberley A Savage

doi:10.3389/fmicb.2018.01811

Abstract

DIBI, a purpose-designed hydroxypyridinone-containing iron-chelating antimicrobial polymer was studied for its anti-staphylococcal activities in vitro in comparison to deferiprone, the chemically related, small molecule hydroxypyridinone chelator. The sensitivities of 18 clinical isolates of Staphylococcus aureus from human, canine and bovine infections were determined. DIBI was strongly inhibitory to all isolates, displaying approximately 100-fold more inhibitory activity than deferiprone when compared on their molar iron-binding capacities. Sensitivity to DIBI was similar for both antibiotic-resistant and -sensitive isolates, including hospital- and community-acquired (United States 300) MRSA. DIBI inhibition was primarily bacteriostatic in nature at low concentration and was reversible by addition of Fe. DIBI also exhibited in vivo anti-infective activity in two distinct MRSA ATCC43300 infection and colonization models in mice. In a superficial skin wound infection model, topical application of DIBI provided a dose-dependent suppression of infection along with reduced wound inflammation. Intranasal DIBI reduced staphylococcal burden by >2 log in a MRSA nares carriage model. DIBI was also examined for its influence on antibiotic activities with a reference isolate ATCC6538, typically utilized to assess new antimicrobials. Sub-bacteriostatic concentrations of DIBI resulted in Fe-restricted growth and this physiological condition displayed increased sensitivity to GEN, CIP, and VAN. DIBI did not impair antibiotic activity but rather it enhanced overall killing. Importantly, recovery growth of survivors that typically followed an initial sub-MIC antibiotic killing phase was substantially suppressed by DIBI for each of the antibiotics examined. DIBI has promise for restricting staphylococcal infection on its own, regardless of the isolate’s animal source or antibiotic resistance profile. DIBI also has potential for use in combination with various classes of currently available antibiotics to improve their responses.

Highlights

Staphylococcus aureus is a normal colonizer of the skin and mucosal surfaces of around 30% of healthy humans but this opportunistic pathogen causes a range of serious wound, lung and bloodstream infections (Liu, 2009; Tong et al, 2015)
DIBI, an iron chelating polymer was found to be strongly inhibitory to a diverse group of S. aureus isolates irrespective of their animal source of origin and irrespective of their antibiotic resistance characteristics
A DIBI dose-dependent reduction in bacterial burdens and a reduction in wound infection-associated inflammation were observed. This evidence was consistent with DIBI sequestering host Fe within wounds or on the mucosal surfaces of the nares, i.e., host Fe supplies that would otherwise have been available to support S. aureus infection

Summary

Introduction

Staphylococcus aureus is a normal colonizer of the skin and mucosal surfaces (e.g., nares) of around 30% of healthy humans but this opportunistic pathogen causes a range of serious wound, lung and bloodstream infections (Liu, 2009; Tong et al, 2015). The staphylococci are prevalent in various infections of companion animals such as with canine otitis where it along with closely related S. pseudintermedius have been found in >36% of all cases (De Martino et al, 2016). The growing spread of methicillin resistant S. aureus (MRSA) among humans (Tong et al, 2015; Ventola, 2015) and from animals in close contact with humans such as dogs (De Martino et al, 2016) dairy cattle or pigs (Vincze et al, 2014; Hamid et al, 2017) along with the significant mortality (14%) seen with invasive human MRSA infection has led to the designation of MRSA as a serious health threat (Frieden, 2013). The prospect for developing an effective staphylococcal vaccine appears to remain poor, possibly due in part to the wide range of infections involved with this microorganism (Proctor, 2012)

Methods

Results

Conclusion