Antibacterial Evaluation of Synthetic Thiazole Compounds In Vitro and In Vivo in a Methicillin-Resistant Staphylococcus aureus (MRSA) Skin Infection Mouse Model.

Haroon Mohammad,Mohamed N Seleem,Mark Cushman

doi:10.1371/journal.pone.0142321

Haroon Mohammad, Mohamed N Seleem + Show 1 more

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https://doi.org/10.1371/journal.pone.0142321

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Abstract

The emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA), including strains resistant to current antibiotics, has contributed to an increase in the number of skin infections reported in humans in recent years. New therapeutic options are needed to counter this public health challenge. The aim of the present study was to examine the potential of thiazole compounds synthesized by our research group to be used topically to treat MRSA skin and wound infections. The broth microdilution method confirmed that the lead thiazole compound and four analogues are capable of inhibiting MRSA growth at concentrations as low as 1.3 μg/mL. Additionally, three compounds exhibited a synergistic relationship when combined with the topical antibiotic mupirocin against MRSA in vitro via the checkerboard assay. Thus the thiazole compounds have potential to be used alone or in combination with mupirocin against MRSA. When tested against human keratinocytes, four derivatives of the lead compound demonstrated an improved toxicity profile (were found to be non-toxic up to a concentration of 20 μg/mL). Utilizing a murine skin infection model, we confirmed that the lead compound and three analogues exhibited potent antimicrobial activity in vivo, with similar capability as the antibiotic mupirocin, as they reduced the burden of MRSA present in skin wounds by more than 90%. Taken altogether, the present study provides important evidence that these thiazole compounds warrant further investigation for development as novel topical antimicrobials to treat MRSA skin infections.

Highlights

Ten percent of all hospital admissions in the United States each year are due to patients suffering from skin and soft tissue infections (SSTIs) [1]
The objectives of the current study were to assess the antibacterial activity of the lead thiazole compound and four analogues (Fig 1) in vitro against antibiotic-resistant S. aureus strains isolated from/responsible for skin infections, to assess the ability of these compounds to be paired with mupirocin as a treatment option against methicillin-resistant Staphylococcus aureus (MRSA), to confirm the compounds have limited toxicity to human keratinocytes, and to verify the thiazole compounds can retain their antimicrobial activity in vivo in an established murine MRSA skin infection model
Previous work has established thiazole compounds 1–5 possess potent antimicrobial activity against MRSA

Summary

Introduction

Ten percent of all hospital admissions in the United States each year are due to patients suffering from skin and soft tissue infections (SSTIs) [1]. 58% of all SSTIs treated in the United States alone were caused by MRSA, according to an epidemiological study of one national health care system [4]. A recent report examining the increase in S. aureus-SSTI hospitalizations in the United States documented a dramatic rise in the annual cost of treating infected patients from $3.36 billion to $4.50 billion (from the years 2001 through 2009) [6]. A recent increase in skin abscesses has been observed and has been associated with a rise in strains of community-associated MRSA (CA-MRSA) [7] Of these strains, MRSA USA300 has been linked most frequently to skin infections in the United States [5, 8]

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