Mechanisms of action and resistance prevention of synergistic thymol and carvacrol combinations with antibiotics in Staphylococcus aureus and Acinetobacter baumannii

doi:10.1007/s13659-025-00518-7

Natural Products and Bioprospecting ›› 2025, Vol. 15 ›› Issue (4): 36-36.DOI: 10.1007/s13659-025-00518-7

• ORIGINAL ARTICLES • Previous Articles Next Articles

Mechanisms of action and resistance prevention of synergistic thymol and carvacrol combinations with antibiotics in Staphylococcus aureus and Acinetobacter baumannii

Cristina Gan¹, Elisa Langa¹, Gang Wang², Fran?oise Van Bambeke², Diego Ballestero¹, María Rosa Pino-Otín¹

1. Universidad San Jorge. Campus Universitario Villanueva de Gállego Autovía A, 23 Zaragoza-Huesca, Km. 510, 50830, Villanueva de Gállego, Saragossa, Spain;
2. Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium

Received:2025-02-10 Accepted:2025-05-04 Online:2025-06-06 Published:2025-08-23
Supported by:
The authors thank the financial support of Gobierno de Aragón: Departamento de Ciencia, Universidad y Sociedad del Conocimiento (Group T67-23R), Cátedra NOVALTIA, Cátedra TEVA and USJ. We also acknowledge Industrias Químicas del Ebro for the predoctoral grant and the mobility grant provided by USJ.

Mechanisms of action and resistance prevention of synergistic thymol and carvacrol combinations with antibiotics in Staphylococcus aureus and Acinetobacter baumannii

Cristina Gan¹, Elisa Langa¹, Gang Wang², Fran?oise Van Bambeke², Diego Ballestero¹, María Rosa Pino-Otín¹

1. Universidad San Jorge. Campus Universitario Villanueva de Gállego Autovía A, 23 Zaragoza-Huesca, Km. 510, 50830, Villanueva de Gállego, Saragossa, Spain;
2. Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium

通讯作者: María Rosa Pino-Otín, E-mail:rpino@usj.es
基金资助:
The authors thank the financial support of Gobierno de Aragón: Departamento de Ciencia, Universidad y Sociedad del Conocimiento (Group T67-23R), Cátedra NOVALTIA, Cátedra TEVA and USJ. We also acknowledge Industrias Químicas del Ebro for the predoctoral grant and the mobility grant provided by USJ.

Abstract

Abstract: The use of natural products as antibiotic adjuvants to enhance efficacy and mitigate resistance is increasingly recognized as a promising strategy. This study explored five novel synergistic antimicrobial combinations (SACs) of carvacrol (CARV) and three already identified SACs of thymol (THY) with chloramphenicol, gentamicin, and streptomycin against Staphylococcus aureus and Acinetobacter baumannii, critical WHO-listed pathogens, and investigated their mechanisms of action and resistance-prevention capabilities. Despite being isomers, CARV and THY exhibited distinct synergistic effects and fractional inhibitory concentration index (FICI) values depending on the antibiotic and bacterial species. The SACs significantly reduced the required antibiotic dose by 4- to 16-fold, with FICI values ranging from 0.25 to 0.5. Growth kinetics revealed that SACs completely inhibited planktonic bacterial growth, outperforming antibiotics alone. Additionally, the SACs demonstrated efficacy in both inhibiting and eradicating biofilms of S. aureus and A. baumannii. Resistance development studies highlighted that neither THY nor CARV induced resistance in these pathogens. Moreover, SACs combining aminoglycosides with THY reduced the emergence of resistance in A. baumannii by up to 32-fold. In S. aureus, THY mitigated gentamicin resistance by 16-fold. CARV exhibited similar, albeit slightly less potent, effects.
Mechanistic investigations revealed that THY and CARV exert antimicrobial action by multiple mechanisms, including bacterial membrane depolarization and disruption, efflux pump inhibition, disrupting ATP metabolism and mitigating oxidative stress induced by antibiotics. These findings highlight the potential of SACs to enhance antibiotic efficacy while preventing resistance, positioning them as strong candidates for innovative antimicrobial therapies against multidrug-resistant pathogens.

Key words: Thymol, Carvacrol, Staphylococcus aureus, Acinetobacter baumannii, Antibiotic resistance

摘要： The use of natural products as antibiotic adjuvants to enhance efficacy and mitigate resistance is increasingly recognized as a promising strategy. This study explored five novel synergistic antimicrobial combinations (SACs) of carvacrol (CARV) and three already identified SACs of thymol (THY) with chloramphenicol, gentamicin, and streptomycin against Staphylococcus aureus and Acinetobacter baumannii, critical WHO-listed pathogens, and investigated their mechanisms of action and resistance-prevention capabilities. Despite being isomers, CARV and THY exhibited distinct synergistic effects and fractional inhibitory concentration index (FICI) values depending on the antibiotic and bacterial species. The SACs significantly reduced the required antibiotic dose by 4- to 16-fold, with FICI values ranging from 0.25 to 0.5. Growth kinetics revealed that SACs completely inhibited planktonic bacterial growth, outperforming antibiotics alone. Additionally, the SACs demonstrated efficacy in both inhibiting and eradicating biofilms of S. aureus and A. baumannii. Resistance development studies highlighted that neither THY nor CARV induced resistance in these pathogens. Moreover, SACs combining aminoglycosides with THY reduced the emergence of resistance in A. baumannii by up to 32-fold. In S. aureus, THY mitigated gentamicin resistance by 16-fold. CARV exhibited similar, albeit slightly less potent, effects.
Mechanistic investigations revealed that THY and CARV exert antimicrobial action by multiple mechanisms, including bacterial membrane depolarization and disruption, efflux pump inhibition, disrupting ATP metabolism and mitigating oxidative stress induced by antibiotics. These findings highlight the potential of SACs to enhance antibiotic efficacy while preventing resistance, positioning them as strong candidates for innovative antimicrobial therapies against multidrug-resistant pathogens.

关键词: Thymol, Carvacrol, Staphylococcus aureus, Acinetobacter baumannii, Antibiotic resistance

Cristina Gan, Elisa Langa, Gang Wang, Fran?oise Van Bambeke, Diego Ballestero, María Rosa Pino-Otín. Mechanisms of action and resistance prevention of synergistic thymol and carvacrol combinations with antibiotics in Staphylococcus aureus and Acinetobacter baumannii[J]. Natural Products and Bioprospecting, 2025, 15(4): 36-36.

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Mechanisms of action and resistance prevention of synergistic thymol and carvacrol combinations with antibiotics in Staphylococcus aureus and Acinetobacter baumannii

Mechanisms of action and resistance prevention of synergistic thymol and carvacrol combinations with antibiotics in Staphylococcus aureus and Acinetobacter baumannii

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