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

Mohammad H, Cushman M, Seleem MN - PLoS ONE (2015)

Bottom Line: 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.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%.

View Article: PubMed Central - PubMed

Affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, Indiana, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Chemical structures of thiazole compounds 1–5 presented in this study.
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pone.0142321.g001: Chemical structures of thiazole compounds 1–5 presented in this study.

Mentions: Previous research by our group has identified a lead disubstituted phenylthiazole compound (compound 1, Fig 1) that exhibited potent antimicrobial activity in vitro against a diverse array of clinically-significant strains of MRSA [17]. Derivatives of the lead 1 were synthesized to elucidate the structure-activity relationships of this compound. These derivatives revealed that the aminoguanidine moiety at thiazole-C5 is critical for antibacterial activity [18]. Furthermore, a nonpolar, hydrophobic group is favored at thiazole-C2. Analogues to the lipophilic alkyl tail of the lead 1 were subsequently constructed in order to enhance the antimicrobial activity of these thiazole compounds, to improve their toxicity profile, and to refine their physicochemical properties [18]. These particular phenylthiazole compounds possess several excellent characteristics in vitro including rapid bactericidal activity against MRSA, a low frequency of bacterial resistance developing, and they have been shown to possess the ability to be used in combination with currently approved antibiotics, such as vancomycin, against MRSA [19]. Studies performed to date indicate these compounds have potential to be used as topical antimicrobials for treatment of MRSA skin infections. 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 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. Confirmation of the ability of these compounds to successfully treat mice infected with a MRSA skin infection will lay the foundation for further assessment of these compounds as novel antimicrobials for treatment of MRSA skin infections.


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

Mohammad H, Cushman M, Seleem MN - PLoS ONE (2015)

Chemical structures of thiazole compounds 1–5 presented in this study.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4633232&req=5

pone.0142321.g001: Chemical structures of thiazole compounds 1–5 presented in this study.
Mentions: Previous research by our group has identified a lead disubstituted phenylthiazole compound (compound 1, Fig 1) that exhibited potent antimicrobial activity in vitro against a diverse array of clinically-significant strains of MRSA [17]. Derivatives of the lead 1 were synthesized to elucidate the structure-activity relationships of this compound. These derivatives revealed that the aminoguanidine moiety at thiazole-C5 is critical for antibacterial activity [18]. Furthermore, a nonpolar, hydrophobic group is favored at thiazole-C2. Analogues to the lipophilic alkyl tail of the lead 1 were subsequently constructed in order to enhance the antimicrobial activity of these thiazole compounds, to improve their toxicity profile, and to refine their physicochemical properties [18]. These particular phenylthiazole compounds possess several excellent characteristics in vitro including rapid bactericidal activity against MRSA, a low frequency of bacterial resistance developing, and they have been shown to possess the ability to be used in combination with currently approved antibiotics, such as vancomycin, against MRSA [19]. Studies performed to date indicate these compounds have potential to be used as topical antimicrobials for treatment of MRSA skin infections. 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 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. Confirmation of the ability of these compounds to successfully treat mice infected with a MRSA skin infection will lay the foundation for further assessment of these compounds as novel antimicrobials for treatment of MRSA skin infections.

Bottom Line: 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.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%.

View Article: PubMed Central - PubMed

Affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, Indiana, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus