Resumen
La resistencia antibiótica constituye un problema creciente debido al aumento de enfermedades asociadas con patógenos resistentes. La respuesta SOS bacteriana es una vía génica de respuesta al estrés cuyo papel principal es la reparación del ADN. Dicha respuesta puede activarse por el daño en el ADN causado por antibióticos y contribuye indirectamente a la aparición de resistencia a través de las polimerasas mutagénicas, la transferencia horizontal de genes y la promoción de la persistencia y la tolerancia bacteriana a los antibióticos. La inhibición de esta vía representa una estrategia prometedora para reducir la generación de variantes resistentes. En este contexto, nuestro objetivo fue evaluar las capacidades antibacterianas, moduladoras de antibióticos e inhibitorias de la respuesta SOS del extracto de Lippia origanoides (ELO) y la pinocembrina, utilizando la cepa Escherichia coli PQ37 y el ensayo SOS Chromotest. El antibiótico evaluado fue el ciprofloxacino, el cual demostró ser un potente inductor de la respuesta SOS en E. coli. En los tratamientos concomitantes con este antibiótico, la pinocembrina (0.097 mM) exhibió un efecto sinérgico sobre la actividad del antibiótico, reduciendo en cerca de cuatro veces su CMI. Además, la pinocembrina inhibió la respuesta SOS inducida por el ciprofloxacino de forma dependiente de la concentración, observándose una inhibición significativa a partir de 0.031 mM (r = - 0.87, p < 0.05). Nuestros resultados indican que la pinocembrina puede actuar como coadyuvante en la terapia antibiótica combinada, dado que potencia su actividad a la vez que inhibe la respuesta SOS bacteriana, un mecanismo que podría minimizar el riesgo de desarrollar resistencia a antibióticos.
Referencias
Abreu, A. C., McBain, A. J., Simões, M. (2012). Plants as sources of new antimicrobials and resistance-modifying agents. Natural Product Reports, 29(9), 1007-1021. https://doi.org/10.1039/c2np20035j
Alam, M. K., Alhhazmi, A., DeCoteau, J. F., Luo, Y., Geyer, C. R. (2016). RecA Inhibitors Potentiate Antibiotic Activity and Block Evolution of Antibiotic Resistance. Cell Chemical Biology, 23(3), 381-391. https://doi.org/10.1016/j.chembiol.2016.02.010
Alpert, P. T. (2016). Superbugs: antibiotic resistance is becoming a major public health concern. Home Health Care Management & Practice, 29(2):130-133. https://doi.org/10.1177/1084822316659285
Andrews, J. M. (2001). Determination of minimum inhibitory concentrations. The Journal Of Antimicrobial Chemotherapy, 48 Suppl 1, 5-16. https://doi.org/10.1093/jac/48.suppl_1.5
Ara, N., Nur, M. H., Amran, M. S., Wahid, M. I., Ahmed, M. (2009). In vitro antimicrobial and cytotoxic activities of leaves and flowers extracts from Lippia alba. Pakistan Journal of Biological Sciences: PJBS, 12(1), 87-90. https://doi.org/10.3923/pjbs.2009.87.90
Arenas, N. E. & Melo, V. M. (2018). Producción pecuaria y emergencia de antibiótico resistencia en Colombia: Revisión sistemática. Infection, 22(2), 110. https://doi.org/10.22354/in.v22i2.717
Babushok, V. I., Linstrom, P. J., Zenkevich, I. G. (2011). Retention indices for frequently reported compounds of plant essential oils. Journal of Physical and Chemical Reference Data, 40, 1-47.
Barreto, H. M., De Lima, I. S., Coelho, K. M. R. N., Osório, L. R., De Almeida Mourão, R., Santos, B. H. C. D., Coutinho, H. D. M., De Abreu, A. P. L., De Medeiros, M. D. G. F., Citó, A. M. D. G. L., Lopes, J. A. D. (2014). Effect of Lippia origanoides H.B.K. Essential oil in the resistance to aminoglycosides in methicillin resistant Staphylococcus aureus. European Journal of Integrative Medicine, 6(5), 560-564. https://doi.org/10.1016/j.eujim.2014.03.011
Barrios, S., Stashenko, E., Ocazionez, R., Fuentes-Lorenzo, J. (2021). Antibacterial activity of essential oils of plants growing in Colombia and its effect on the activity of β-lactam antibiotics. Revista Cubana de Farmacia, 54. e627.
Bellio, P., Brisdelli, F., Perilli, M., Sabatini, A., Bottoni, C., Segatore, B., Setacci, D., Amicosante, G., Celenza, G. (2014). Curcumin inhibits the SOS response induced by levofloxacin in Escherichia coli. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 21(4), 430-434. https://doi.org/10.1016/j.phymed.2013.10.011
Bunnell, B. E., Escobar, J. F., Bair, K. L., Sutton, M. D., Crane, J. K. (2017). Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli. PloS one, 12(5), e0178303. https://doi.org/10.1371/journal.pone.0178303
Chatterjee, C., Mohan, G. R., Chinnasamy, H. V., Biswas, B., Sundaram, V., Srivastava, A., Matheshwaran, S. (2024). Anti-mutagenic agent targeting LexA to combat antimicrobial resistance in mycobacteria. Journal Of Biological Chemistry, 300(9), 107650. https://doi.org/10.1016/j.jbc.2024.107650
Cirz, R. T., Chin, J. K., Andes, D. R., de Crécy-Lagard, V., Craig, W. A., Romesberg, F. E. (2005). Inhibition of mutation and combating the evolution of antibiotic resistance. PLoS Biology, 3(6), e176. https://doi.org/10.1371/journal.pbio.0030176
Cline, D. J., Holt, S. L., Singleton, S. F. (2007). Inhibition of Escherichia coli RecA by rationally redesigned N-terminal helix. Organic and Biomolecular Chemistry, 5(10), 1525. https://doi.org/10.1039/b703159a
Cos, P., Vlietinck, A. J., Berghe, D. V., Maes, L. (2006). Anti-infective potential of natural products: how to develop a stronger in vitro 'proof-of-concept'. Journal of Ethnopharmacology, 106(3), 290–302. https://doi.org/10.1016/j.jep.2006.04.003
Courcelle, J., Khodursky, A., Peter, B., Brown, P. O., Hanawalt, P. C. (2001). Comparative gene expression profiles following UV exposure in wild-type and SOS-deficient Escherichia coli. Genetics, 158(1), 41–64. https://doi.org/10.1093/genetics/158.1.41
Crane, J. K., Alvarado, C. L., Sutton, M. D. (2021). Role of the SOS Response in the Generation of Antibiotic Resistance In Vivo. Antimicrobial Agents and Chemotherapy, 65(7), e0001321. https://doi.org/10.1128/AAC.00013-21
de Castro, J., Trujillo, N., Ocazionez, R., Stashenko, E., Fuentes-Lorenzo, J. (2025). Antibacterial Activity of Plant Extracts and Their Effect on β-Lactam Antibiotic Activity in Methicillin-Resistant Staphylococcus aureus. Latin American Journal of Pharmacy, 44, 269-277.
Dias, K. J. S. O., Miranda, G. M., Bessa, J. R., Araújo, A. C. J., Freitas, P. R., Almeida, R. S., Paulo, C. L. R., Neto, J. B. A., Coutinho, H. D. M., Ribeiro-Filho, J. (2022). Terpenes as bacterial efflux pump inhibitors: A systematic review. Frontiers in Pharmacology, 13, 953982. https://doi.org/10.3389/fphar.2022.953982
Elfadadny, A., Ragab, R. F., AlHarbi, M., Badshah, F., Ibáñez-Arancibia, E., Farag, A., Hendawy, A. O., De Los Ríos-Escalante, P. R., Aboubakr, M., Zakai, S. A., Nageeb, W. M. (2024). Antimicrobial resistance of Pseudomonas aeruginosa: navigating clinical impacts, current resistance trends, and innovations in breaking therapies. Frontiers in Microbiology, 15, 1374466. https://doi.org/10.3389/fmicb.2024.1374466
Fernández De Henestrosa, A. R., Ogi, T., Aoyagi, S., Chafin, D., Hayes, J. J., Ohmori, H., Woodgate, R. (2000). Identification of additional genes belonging to the LexA regulon in Escherichia coli. Molecular Microbiology, 35(6), 1560–1572. https://doi.org/10.1046/j.1365-2958.2000.01826.x
Fuentes, J. L., García-Forero, A., Quintero Ruiz, N., Prada Medina, C. A., Rey Castellanos, N., Franco Niño, D. A., Contreras García, D. A., Córdoba Campo, Y., Stashenko, E. E. (2017). The SOS Chromotest applied for screening plant antigenotoxic agents against ultraviolet radiation. Photochemical and Photobiological Sciences: Official journal of the European Photochemistry Association and the European Society for Photobiology, 16(9), 1424-1434. https://doi.org/10.1039/c7pp00024c
Fuentes, J. L., Vernhe, M., Cuetara, E. B., Sánchez-Lamar, A., Santana, J. L., Llagostera, M. (2006). Tannins from barks of Pinus caribaea protect Escherichia coli cells against DNA damage induced by γ-rays. Fitoterapia, 77(2), 116-120. https://doi.org/10.1016/j.fitote.2005.11.014
Fuentes, J.L., Villamizar-Mantilla, D.A., Flores-González, S.J., Núñez, L.A., Stashenko, E.E. (2021) Plants growing in Colombia as sources of active ingredients for sunscreens. International Journal of Radiation Biology, 97(12), 1705-1715. https://doi.org/10.1080/09553002.2021.1987564
García-Forero, A., Villamizar Mantilla, D. A., Núñez, L. A., Ocazionez, R. E., Stashenko, E. E., Fuentes, J. L. (2019). Photoprotective and Antigenotoxic Effects of the Flavonoids Apigenin, Naringenin and Pinocembrin. Photochemistry and Photobiology, 95(4), 1010-1018. https://doi.org/10.1111/php.13085
Górniak, I., Bartoszewski, R., Króliczewski, J. (2019). Comprehensive review of antimicrobial activities of plant flavonoids. Phytochemistry Reviews, 18(1), 241-272. https://doi.org/10.1007/s11101-018-9591-z
Hall, M. J., Middleton, R. F., Westmacott, D. (1983). The fractional inhibitory concentration (FIC) index as a measure of synergy. The Journal of Antimicrobial Chemotherapy, 11(5), 427-433. https://doi.org/10.1093/jac/11.5.427
Henrikus, S. S., van Oijen, A. M., Robinson, A. (2018). Specialised DNA polymerases in Escherichia coli: roles within multiple pathways. Current Genetics, 64(6), 1189-1196. https://doi.org/10.1007/s00294-018-0840-x
Ikehata, H. & Ono, T. (2011). The mechanisms of UV mutagenesis. Journal of Radiation Research, 52(2), 115-125. https://doi.org/10.1269/jrr.10175
Jaktaji, R. P. & Rezaei, S. M. N. (2021). Inactivation of UmuC Protein Significantly Reduces Resistance to Ciprofloxacin and SOS Mutagenesis in Escherichia coli Mutants Harboring Intact umuD Gene. Jundishapur Journal of Microbiology, 13(12). https://doi.org/10.5812/jjm.111828
Kasimanickam, V., Kasimanickam, M., Kasimanickam, R. (2021). Antibiotics Use in Food Animal Production: Escalation of Antimicrobial Resistance: Where Are We Now in Combating AMR? Medical Sciences (Basel, Switzerland), 9(1), 14. https://doi.org/10.3390/medsci9010014
Kaur, S., Hariharan, S., Dharmaraj, S. (2020). Superbugs: the powerful warriors. International Journal of Pharmaceutical Sciences and Research, 11(4), 1506-26. https://doi.org/10.13040/ijpsr.0975-8232.11(4) 1506-26.
Klančnik, A., Šimunović, K., Kovac, J., Sahin, O., Wu, Z., Vučković, D., Abram, M., Zhang, Q., Možina, S. S. (2019). The Anti-Campylobacter Activity and Mechanisms of Pinocembrin Action. Microorganisms, 7(12), 675. https://doi.org/10.3390/microorganisms7120675
Kohanski, M. A., DePristo, M. A., Collins, J. J. (2010). Sublethal Antibiotic Treatment Leads to Multidrug Resistance via Radical-Induced Mutagenesis. Molecular Cell, 37(3), 311-320. https://doi.org/10.1016/j.molcel.2010.01.003
Konaté, K., Mavoungou, J. F., Lepengué, A. N., Aworet-Samseny, R. R., Hilou, A., Souza, A., Dicko, M. H., M'batchi, B. (2012). Antibacterial activity against β- lactamase producing Methicillin and Ampicillin-resistants Staphylococcus aureus: Fractional Inhibitory Concentration Index (FICI) determination. Annals of Clinical Microbiology and Antimicrobials, 11, 18. https://doi.org/10.1186/1476-0711-11-18
Kumar, S., Chen, C., Indugu, N., Werlang, G. O., Singh, M., Kim, W. K., Thippareddi, H. (2018). Effect of antibiotic withdrawal in feed on chicken gut microbial dynamics, immunity, growth performance and prevalence of foodborne pathogens. PloS one, 13(2), e0192450. https://doi.org/10.1371/journal.pone.0192450
Lee, A. M. & Singleton, S. F. (2004). Inhibition of the Escherichia coli RecA protein: zinc(II), copper(II) and mercury(II) trap RecA as inactive aggregates. Journal of Inorganic Biochemistry, 98(11), 1981-1986. https://doi.org/10.1016/j.jinorgbio.2004.08.018
Lee, A. M., Ross, C. T., Zeng, B. B., Singleton, S. F. (2005). A molecular target for suppression of the evolution of antibiotic resistance: inhibition of the Escherichia coli RecA protein by N(6)-(1-naphthyl)-ADP. Journal of Medicinal Chemistry, 48(17), 5408-5411. https://doi.org/10.1021/jm050113z
Little, J. W., Edmiston, S. H., Pacelli, L. Z., Mount, D. W. (1980). Cleavage of the Escherichia coli lexA protein by the recA protease. Proceedings of the National Academy of Sciences of the United States of America, 77(6), 3225-3229. https://doi.org/10.1073/pnas.77.6.3225
Liu, G., Liang, J., Wang, X., Li, Z., Wang, W., Guo, N., Wu, X., Shen, F., Xing, M., Liu, L., Li, L., Liu, M., Yu, L. (2011). In Vitro Synergy of Biochanin A and Ciprofloxacin against Clinical Isolates of Staphylococcus aureus. Molecules, 16(8), 6656-6666. https://doi.org/10.3390/molecules16086656
Machuca, J., Recacha, E., Gallego-Mesa, B., Diaz-Diaz, S., Rojas-Granado, G., García-Duque, A., Docobo-Pérez, F., Blázquez, J., Rodríguez-Rojas, A., Pascual, A., Rodríguez-Martínez, J. M. (2021). Effect of RecA inactivation on quinolone susceptibility and the evolution of resistance in clinical isolates of Escherichia coli. The Journal of Antimicrobial Chemotherapy, 76(2), 338-344. https://doi.org/10.1093/jac/dkaa448
Mamber, S. W., Kolek, B., Brookshire, K. W., Bonner, D. P., Fung-Tomc, J. (1993). Activity of quinolones in the Ames Salmonella TA102 mutagenicity test and other bacterial genotoxicity assays. Antimicrobial Agents and Chemotherapy, 37(2), 213-217. https://doi.org/10.1128/AAC.37.2.213
Martínez, A., Manrique-Moreno, M., Klaiss-Luna, M. C., Stashenko, E., Zafra, G., Ortiz, C. (2021). Effect of Essential Oils on Growth Inhibition, Biofilm Formation and Membrane Integrity of Escherichia coli and Staphylococcus aureus. Antibiotics (Basel, Switzerland), 10(12), 1474. https://doi.org/10.3390/antibiotics10121474
Mazanko, M., Prazdnova, E., Rudoy, D., Ermakov, A., Olshevskaya, A., Maltseva, T. (2020). Extracts of medical plants suppress the SOS response and reduce mutagenesis in E. coli. E3S Web of Conferences, 175, 01010. https://doi.org/10.1051/e3sconf/202017501010
Memar, M. Y., Yekani, M., Celenza, G., Poortahmasebi, V., Naghili, B., Bellio, P., Baghi, H. B. (2020). The central role of the SOS DNA repair system in antibiotics resistance: A new target for a new infectious treatment strategy. Life Sciences, 262, 118562. https://doi.org/10.1016/j.lfs.2020.118562
Mo, C. Y., Manning, S. A., Roggiani, M., Culyba, M. J., Samuels, A. N., Sniegowski, P. D., Goulian, M., Kohli, R. M. (2016). Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics. mSphere, 1(4), e00163-16. https://doi.org/10.1128/mSphere.00163-16
Naghavi, M., Vollset, S. E., Ikuta, K. S., Swetschinski, L. R., Gray, A. P., Wool, E. E., Aguilar, G. R., Mestrovic, T., Smith, G., Han, C., Hsu, R. L., Chalek, J., Araki, D. T., Chung, E., Raggi, C., Hayoon, A. G., Weaver, N. D., Lindstedt, P. A., Smith, A. E., Aziz, S. (2024). Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050. The Lancet, 404(10459), 1199-1226. https://doi.org/10.1016/s0140-6736(24)01867-1
Nhung, N. T., Chansiripornchai, N., Carrique-Mas, J. J. (2017). Antimicrobial Resistance in Bacterial Poultry Pathogens: A Review. Frontiers in Veterinary Science, 4, 284486. https://doi.org/10.3389/fvets.2017.00126
Ojha, D. & Patil, K. N. (2019). p-Coumaric acid inhibits the Listeria monocytogenes RecA protein functions and SOS response: An antimicrobial target. Biochemical and Biophysical Research Communications, 517(4), 655-661. https://doi.org/10.1016/j.bbrc.2019.07.093
Qin, T. T., Kang, H. Q., Ma, P., Li, P. P., Huang, L. Y., Gu, B. (2015). SOS response and its regulation on the fluoroquinolone resistance. Annals of translational medicine, 3(22), 358. https://doi.org/10.3978/j.issn.2305-5839.2015.12.09
Quillardet, P. & Hofnung, M. (1985). The SOS Chromotest, a colorimetric bacterial assay for genotoxins: procedures. Mutation Research/Environmental Mutagenesis and Related Subjects, 147(3), 65-78. https://doi.org/10.1016/0165-1161(85)90020-2
Quintero-Ruiz, N., Córdoba-Campo, Y., Stashenko, E. E., Fuentes, J. L. (2017). Antigenotoxic Effect Against Ultraviolet Radiation-induced DNA Damage of the Essential Oils from Lippia Species. Photochemistry and Photobiology, 93(4), 1063-1072. https://doi.org/10.1111/php.12735
R Core Team (2024). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. https://www.R-project.org/
Radman, M. (1975). SOS repair hypothesis: phenomenology of an inducible DNA repair which is accompanied by mutagenesis. Basic Life Sciences, 5A, 355-367. https://doi.org/10.1007/978-1-4684-2895-7_48
Rasul, A., Millimouno, F. M., Eltayb, W. A., Ali, M., Li, J., Li, X. (2013). Pinocembrin: A Novel Natural Compound with Versatile Pharmacological and Biological Activities. BioMed Research International, 2013, 1-9. https://doi.org/10.1155/2013/379850
Ribeiro, F. P., Santana de Oliveira, M., de Oliveira Feitosa, A., Santana Barbosa Marinho, P., Moacir do Rosario Marinho, A., de Aguiar Andrade, E. H., Favacho Ribeiro, A. (2021). Chemical Composition and Antibacterial Activity of the Lippia origanoides Kunth Essential Oil from the Carajás National Forest, Brazil. Evidence-based Complementary and Alternative Medicine: eCAM, 9930336. https://doi.org/10.1155/2021/9930336
Scallan, E., Hoekstra, R. M., Angulo, F. J., Tauxe, R. V., Widdowson, M., Roy, S. L., Jones, J. L., Griffin, P. M. (2010). Foodborne Illness Acquired in the United States—Major Pathogens. Emerging Infectious Diseases, 17(1), 7-15. https://doi.org/10.3201/eid1701.p11101
Selwood, T., Larsen, B. J., Mo, C. Y., Culyba, M. J., Hostetler, Z. M., Kohli, R. M., Reitz, A. B., Baugh, S. D. P. (2018). Advancement of the 5-Amino-1-(Carbamoylmethyl)-1H-1,2,3-Triazole-4-Carboxamide Scaffold to Disarm the Bacterial SOS Response. Frontiers in Microbiology, 9, 2961. https://doi.org/10.3389/fmicb.2018.02961
Şener, B. & Gökalsın, B. (2026). Inhibition of the SOS response by olivetol improves the efficacy of DNA-damaging antibiotics in Escherichia coli. The Journal of Antibiotics, 79(8), 542-553. https://doi.org/10.1038/s41429-026-00935-x
Shinagawa, H. (1996). SOS response as an adaptive response to DNA damage in prokaryotes. EXS, 77, 221-235. https://doi.org/10.1007/978-3-0348-9088-5_14
Vicuña, G. C., Stashenko, E. E., Fuentes, J. L. (2010). Chemical composition of the Lippia origanoides essential oils and their antigenotoxicity against bleomycin-induced DNA damage. Fitoterapia, 81(5), 343-349. https://doi.org/10.1016/j.fitote.2009.10.008
Wang, P., Zhang, X., Wang, L., Zhen, Z., Tang, M., Li, J. (2010). Subinhibitory concentrations of ciprofloxacin induce SOS response and mutations of antibiotic resistance in bacteria. Annals of Microbiology, 60(3), 511-517. https://doi.org/10.1007/s13213-010-0080-x
Wu, Y., Chen, J., Wei, W., Miao, Y., Liang, C., Wu, J., Huang, X., Yin, L., Geng, Y., Chen, D., Ouyang, P. (2022). A study of the antibacterial mechanism of pinocembrin against multidrug-resistant Aeromonas hydrophila. International Microbiology, 25(3), 605-613. https://doi.org/10.1007/s10123-022-00245-w
Yakimov, A., Bakhlanova, I., Baitin, D. (2021). Targeting evolution of antibiotic resistance by SOS response inhibition. Computational and Structural Biotechnology Journal, 19, 777-783. https://doi.org/10.1016/j.csbj.2021.01.003
Yakimov, A., Pobegalov, G., Bakhlanova, I., Khodorkovskii, M., Petukhov, M., Baitin, D. (2017). Blocking the RecA activity and SOS-response in bacteria with a short α-helical peptide. Nucleic Acids Research, 45(16), 9788-9796. https://doi.org/10.1093/nar/gkx687

Esta obra está bajo una licencia internacional Creative Commons Atribución-NoComercial-SinDerivadas 4.0.
Derechos de autor 2026 Revista de la Academia Colombiana de Ciencias Exactas, Físicas y Naturales

