The use of 4-Hexylresorcinol as antibiotic adjuvant

Ever decreasing efficiency of antibiotic treatment due to growing antibiotic resistance of pathogenic bacteria is a critical issue in clinical practice. The two generally accepted major approaches to this problem are the search for new antibiotics and the development of antibiotic adjuvants to enhance the antimicrobial activity of known compounds. It was therefore the aim of the present study to test whether alkylresorcinols, a class of phenolic lipids, can be used as adjuvants to potentiate the effect of various classes of antibiotics. Alkylresorcinols were combined with 12 clinically used antibiotics. Growth-inhibiting activity against a broad range of pro- and eukaryotic microorganisms was determined. Test organisms did comprise 10 bacterial and 2 fungal collection strains, including E. coli and S. aureus, and clinical isolates of K. pneumoniae. The highest adjuvant activity was observed in the case of 4-hexylresorcinol (4-HR), a natural compound found in plants with antimicrobial activity. 50% of the minimal inhibitory concentration (MIC) of 4-HR caused an up to 50-fold decrease in the MIC of antibiotics of various classes. Application of 4-HR as an adjuvant revealed its efficiency against germination of bacterial dormant forms (spores) and prevented formation of antibiotic-tolerant persister cells. Using an in vivo mouse model of K. pneumoniae-induced sepsis, we could demonstrate that the combination of 4-HR and polymyxin was highly effective. 75% of animals were free of infection after treatment as compared to none of the animals receiving the antibiotic alone. We conclude that alkylresorcinols such as 4-HR can be used as an adjuvant to increase the efficiency of several known antibiotics. We suggest that by this approach the risk for development of genetically determined antibiotic resistance can be minimized due to the multimodal mode of action of 4-HR. © 2020 Nikolaev et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Nikolaev Y.A.1 , Tutel’yan A.V.2 , Loiko N.G.1 , Buck J.3 , Sidorenko S.V.5, 6 , Lazareva I.5, 6 , Gostev V.5, 6 , Manzen’yuk O.Y.7 , Shemyakin I.G.7 , Abramovich R.A. 4 , Huwyler J.3 , El’-Registan G.I.1
Public Library of Science
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9 September
  • 1 Federal Research Centre “Fundamentals of Biotechnology”, Russian Academy of Sciences, Moscow, Russian Federation
  • 2 Central Research Institute of Epidemiology of Russian Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor) and I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the, Russian Federation (Sechenov University), Moscow, Russian Federation
  • 3 Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
  • 4 Peoples’ Friendship University of Russia (RUDN University), Moscow, Russian Federation
  • 5 Pediatric Research and Clinical Center for Infectious Diseases, Saint Petersburg, Russian Federation
  • 6 I.I. Mechnikov North Western State Medical University, St Petersburg, Russian Federation
  • 7 State Research Center for Applied Microbiology and Biotechnology, Russian Federal Service for Surveillance on Consumer Rights Protection and Human Welfare (Rospotrebnadzor), Obolensk, Russian Federation
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