Diflunisal and Analogue Pharmacophores Mediating Suppression of Virulence Phenotypes in <i>Staphylococcus aureus</i>
Invasive methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) infections are leading causes of morbidity and mortality that are complicated by increasing resistance to conventional antibiotics. Thus, minimizing virulence and enhancing antibiotic efficacy against MRSA is a public hea...
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| Format: | Article |
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MDPI AG
2023-07-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/12/7/1180 |
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| author | Liana C. Chan Hong K. Lee Ling Wang Siyang Chaili Yan Q. Xiong Arnold S. Bayer Richard A. Proctor Michael R. Yeaman |
| author_facet | Liana C. Chan Hong K. Lee Ling Wang Siyang Chaili Yan Q. Xiong Arnold S. Bayer Richard A. Proctor Michael R. Yeaman |
| author_sort | Liana C. Chan |
| collection | DOAJ |
| description | Invasive methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) infections are leading causes of morbidity and mortality that are complicated by increasing resistance to conventional antibiotics. Thus, minimizing virulence and enhancing antibiotic efficacy against MRSA is a public health imperative. We originally demonstrated that diflunisal (DIF; [2-hydroxy-5-(2,4-difluorophenyl) benzoic acid]) inhibits <i>S. aureus</i> virulence factor expression. To investigate pharmacophores that are active in this function, we evaluated a library of structural analogues for their efficacy to modulate virulence phenotypes in a panel of clinically relevant <i>S. aureus</i> isolates in vitro. Overall, the positions of the phenyl, hydroxyl, and carboxylic moieties and the presence or type of halogen (F vs. Cl) influenced the efficacy of compounds in suppressing hemolysis, proteolysis, and biofilm virulence phenotypes. Analogues lacking halogens inhibited proteolysis to an extent similar to DIF but were ineffective at reducing hemolysis or biofilm production. In contrast, most analogues lacking the hydroxyl or carboxylic acid groups did not suppress proteolysis but did mitigate hemolysis and biofilm production to an extent similar to DIF. Interestingly, chirality and the substitution of fluorine with chlorine resulted in a differential reduction in virulence phenotypes. Together, this pattern of data suggests virulence-suppressing pharmacophores of DIF and structural analogues integrate halogen, hydroxyl, and carboxylic acid moiety stereochemistry. The anti-virulence effects of DIF were achieved using concentrations that are safe in humans, do not impair platelet antimicrobial functions, do not affect <i>S. aureus</i> growth, and do not alter the efficacy of conventional antibiotics. These results offer proof of concept for using novel anti-virulence strategies as adjuvants to antibiotic therapy to address the challenge of MRSA infection. |
| first_indexed | 2024-03-11T01:21:48Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-11T01:21:48Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-a160510e6a7142b3a32dd3f156556b752023-11-18T18:03:24ZengMDPI AGAntibiotics2079-63822023-07-01127118010.3390/antibiotics12071180Diflunisal and Analogue Pharmacophores Mediating Suppression of Virulence Phenotypes in <i>Staphylococcus aureus</i>Liana C. Chan0Hong K. Lee1Ling Wang2Siyang Chaili3Yan Q. Xiong4Arnold S. Bayer5Richard A. Proctor6Michael R. Yeaman7Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502, USADivision of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502, USADivision of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502, USAVanderbilt Eye Institute, Vanderbilt University Medical Center, 2311 Pierce Ave., Nashville, TN 37232, USADivision of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, CA 90502, USADivision of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, CA 90502, USADepartments of Medical Microbiology & Immunology and Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USADivision of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502, USAInvasive methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) infections are leading causes of morbidity and mortality that are complicated by increasing resistance to conventional antibiotics. Thus, minimizing virulence and enhancing antibiotic efficacy against MRSA is a public health imperative. We originally demonstrated that diflunisal (DIF; [2-hydroxy-5-(2,4-difluorophenyl) benzoic acid]) inhibits <i>S. aureus</i> virulence factor expression. To investigate pharmacophores that are active in this function, we evaluated a library of structural analogues for their efficacy to modulate virulence phenotypes in a panel of clinically relevant <i>S. aureus</i> isolates in vitro. Overall, the positions of the phenyl, hydroxyl, and carboxylic moieties and the presence or type of halogen (F vs. Cl) influenced the efficacy of compounds in suppressing hemolysis, proteolysis, and biofilm virulence phenotypes. Analogues lacking halogens inhibited proteolysis to an extent similar to DIF but were ineffective at reducing hemolysis or biofilm production. In contrast, most analogues lacking the hydroxyl or carboxylic acid groups did not suppress proteolysis but did mitigate hemolysis and biofilm production to an extent similar to DIF. Interestingly, chirality and the substitution of fluorine with chlorine resulted in a differential reduction in virulence phenotypes. Together, this pattern of data suggests virulence-suppressing pharmacophores of DIF and structural analogues integrate halogen, hydroxyl, and carboxylic acid moiety stereochemistry. The anti-virulence effects of DIF were achieved using concentrations that are safe in humans, do not impair platelet antimicrobial functions, do not affect <i>S. aureus</i> growth, and do not alter the efficacy of conventional antibiotics. These results offer proof of concept for using novel anti-virulence strategies as adjuvants to antibiotic therapy to address the challenge of MRSA infection.https://www.mdpi.com/2079-6382/12/7/1180diflunisalanaloguesvirulencepharmacophore<i>Staphylococcus aureus</i>antimicrobial |
| spellingShingle | Liana C. Chan Hong K. Lee Ling Wang Siyang Chaili Yan Q. Xiong Arnold S. Bayer Richard A. Proctor Michael R. Yeaman Diflunisal and Analogue Pharmacophores Mediating Suppression of Virulence Phenotypes in <i>Staphylococcus aureus</i> Antibiotics diflunisal analogues virulence pharmacophore <i>Staphylococcus aureus</i> antimicrobial |
| title | Diflunisal and Analogue Pharmacophores Mediating Suppression of Virulence Phenotypes in <i>Staphylococcus aureus</i> |
| title_full | Diflunisal and Analogue Pharmacophores Mediating Suppression of Virulence Phenotypes in <i>Staphylococcus aureus</i> |
| title_fullStr | Diflunisal and Analogue Pharmacophores Mediating Suppression of Virulence Phenotypes in <i>Staphylococcus aureus</i> |
| title_full_unstemmed | Diflunisal and Analogue Pharmacophores Mediating Suppression of Virulence Phenotypes in <i>Staphylococcus aureus</i> |
| title_short | Diflunisal and Analogue Pharmacophores Mediating Suppression of Virulence Phenotypes in <i>Staphylococcus aureus</i> |
| title_sort | diflunisal and analogue pharmacophores mediating suppression of virulence phenotypes in i staphylococcus aureus i |
| topic | diflunisal analogues virulence pharmacophore <i>Staphylococcus aureus</i> antimicrobial |
| url | https://www.mdpi.com/2079-6382/12/7/1180 |
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