Resumen
Introducción: El aumento de bacterias resistentes a múltiples fármacos destaca la necesidad de mejorar las terapias antimicrobianas. Las bombas de eflujo, que reducen la concentración de antimicrobianos en las bacterias, son clave en la resistencia, mecanismos que disminuyen la concentración de antimicrobianos en las bacterias, contribuyendo a la resistencia. Objetivo: evaluar el efecto del inhibidor de bombas de eflujo Phenylalanine-arginine β-naphthylamide sobre la resistencia bacteriana a los antibióticos ceftazidima, clortetraciclina, ciprofloxacina, ceftriaxona, ampicilina y gentamicina en bacilos gram negativos con múltiples genes de BLEE aisladas. Materiales y Métodos: se realizó un estudio experimental con el propósito de analizar los aislamientos de bacilos gram negativos multirresistentes asociados a infecciones procedentes de una Institución prestadora de servicios de salud de Boyacá, para esto, a partir de 81 aislamientos bacterianos se detectaron genes de resistencia antibiótico en 70 cepas mediante reacción en cadena de la polimerasa convencional y secuenciación tipo Sanger. Resultados: en los 70 aislamientos analizados se evidenció la presencia de determinantes genéticos de resistencia a antibióticos betalactámicos como: blaTEM1, blaSHV1, blaSHV2 y blaCTM-X, con predominancia del gen blaSHV. Conclusiones: el ensayo de interacción mostró qué en cepas multirresistentes, la terapia conjunta con inhibidores de bombas de expulsión puede ser una alternativa para el tratamiento, sin embargo, debido a la gran diversidad de las bombas de eflujo, se deben evaluar otras familias de inhibidores para identificar los que sean eficientes en un mayor número de cepas.
Referencias
Organización Mundial de la Salud [Internet]. Resistencia a los antimicrobianos; 17 de noviembre del 2021 [citado 11 de enero de 2024]. Disponible en: https://www.who.int/es/newsroom/fact-sheets/detail/antimicrobial-resistance
Castro LT, Torres MI, Castañeda LM, López DP, Prada CF. Caracterización fenotípica de bacilos Gram negativos con betalactamasas de espectro extendido y carbapenemasas. Rev Investig. Salud Univ Boyacá. 2015;2(2):116-130.
Baron SA, Rolain JM. Efflux pump inhibitor CCCP to rescue colistin susceptibility in mcr-1 plasmidmediated colistin-resistant strains and Gramnegative bacteria.J Antimicrob Chemother. 2018;73(7):1862-1871.
Chetri S. The culmination of multidrug-resistant efflux pumps vs. meager antibiotic arsenal era: Urgent need for an improved new generation of EPIs. Front Microbiol. 2023;14:1149418.
Sharma A, Gupta VK, Pathania R. Efflux pump inhibitors for bacterial pathogens: From bench to bedside. Indian J Med Res. 2019;149(2):129-145.
Nolivos S, Cayron J, Dedieu A, Page A, Delolme F, Lesterlin C. Role of AcrAB-TolC multidrug efflux pump in drug-resistance acquisition by plasmid transfer. Science. 2019;364(6442):778-782.
Misra R, Morrison KD, Cho HJ, Khuu T. Importance of Real-Time Assays To Distinguish Multidrug Efflux Pump-Inhibiting and Outer Membrane-Destabilizing Activities in Escherichia coli. J Bacteriol. 2015;197(15):2479-2488.
Lamut A, Peterlin Masic L, Kikelj D, Tomasic T. Efflux pump inhibitors of clinically relevant multidrug resistant bacteria. Med Res Rev. 2019;39(6):2460-504.
Park YK, Ko KS. Effect of carbonyl cyanide 3-chlorophenylhydrazone (CCCP) on killing Acinetobacter baumannii by colistin. J Microbiol. 2015;53(1):53-9.
Parker A, Gottesman S. Small RNA Regulation of TolC, the Outer Membrane Component of Bacterial Multidrug Transporters. J Bacteriol 2016;198(7):1101-13.
Aparna V, Dineshkumar K, Mohanalakshmi N, Velmurugan D, Hopper W. Identification of Natural Compound Inhibitors for Multidrug Efflux Pumps of Escherichia coli and Pseudomonas aeruginosa using in Silico High-Throughput Virtual Screening and In Vitro Validation. PLoS One. 2014;9(7):e101840.
Dwivedi GR, Tiwari N, Singh A, Kumar A, Roy S, Negi AS, et al. Gallic acid-based indanone derivative interacts synergistically with tetracycline by inhibiting efflux pump in multidrug resistant E. coli. Appl Microbiol Biotechnol.. 2016;100(5):2311-25.
Dwivedi GR, Maurya A, Yadav DK, Singh V, Khan F, Gupta MK, et al. Synergy of clavine alkaloid “chanoclavine” with tetracycline against multidrug-resistant E. coli. J Biomol Struct Dyn. 2019;37(5):1307-25.
Angarita Merchán M, Di Filippo Iriarte G, Mora Moreno DP, Ferrebuz Cardozo AJ. Perfil de resistencia de microorganismos circulantes en una Institución Prestadora de Servicios de salud en el Departamento de Boyacá, 2018. Revista Investig. Salud Univ. Boyacá. 2019;6(1):120-44.
Paterson DL, Hujer KM, Hujer AM, Yeiser B, Bonomo MD, Rice LB, et al. Extended-Spectrum beta-Lactamases in Klebsiella pneumoniae Bloodstream Isolates from Seven Countries: Dominance and Widespread Prevalence of SHVand CTX-M-Type beta-Lactamases. Antimicrob Agents Chemother. 2003;47(11):3554-60.
Orhan G, Bayram A, Zer Y, Balci I. Synergy tests by E test and checkerboard methods of antimicrobial combinations against Brucella melitensis. J Clin Microbiol. 2005;43(1):140-3.
Berenbaum MC. A method for testing for synergy with any number of agents. J Infect Dis. 1978;137(2):122-30.
Odds FC. Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother. 2003;52(1):1.
López DP, Castro LT, Prada CF, Torres MI. Molecular Characterization of MultidrugResistant Bacteria Isolated from a Boyacá Hospital, Colombia. The Internet journal of microbiology. 2018;15(1):1-12.
Kumar S, Stecher G, Li M, Knyaz C, Tamura K. MEGA X: Molecular Evolutionary Genetics Analysis across Computing Platforms. Mol Biol Evol. 2018;35(6):1547-9.
Velandia DPL, Torres MI, Castañeda LM, Prada CF. Determinación de genes que codifican la resistencia de betalactamasas de espectro extendido en bacilos Gram negativos aislados de urocultivos. Investig Salud Univ Boyacá.2016; 3(2):107-126.
Peymani A, Naserpour T, Zare E, Azarhoosh K. Distribution of blaTEM, blaSHV, and blaCTX-M genes among ESBL-producing P. aeruginosa isolated from Qazvin and Tehran hospitals, Iran. J Prev Med Hyg. 2017; 58(2):155-160.
Zanguña LF, Torres MI, Di Filippo G. Perfil de tolerancia al triclosán y detección de los genes MexA, MexC, AcrB y oqxA relacionados con la expresión de bombas de expulsión en aislados clínicos del género Enterobacter aerogenes y Enterobacter cloacae. Investig Salud Univ Boyacá. 2020; 7(1):102-117.
Li XZ, Nikaido H. Efflux-mediated drug resistance in bacteria. Drugs. 2004;64(2):159-204.
Murakami S, Nakashima R, Yamashita E, Matsumoto T, Yamaguchi A. Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature. 2006;443(7108):173- 179.
Schuster S, Bohnert JA, Vavra M, Rossen JW, Kern WV. Proof of an Outer Membrane Target of the Efflux Inhibitor Phe-Arg-beta-Naphthylamide from Random Mutagenesis. Molecules. 2019;24(3):470.
Zhang W, Guo Y, Yang Y, Dong D, Zheng Y, Zhu D, et al. Study of In Vitro Synergistic Bactericidal Activity of Dual beta-Lactam Antibiotics Against KPC-2-Producing Klebsiella pneumoniae. Microb Drug Resist. 2020;26(3):204-210.
Vidaillac C, Benichou L, Duval RE. In vitro synergy of colistin combinations against colistin-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae isolates. Antimicrob Agents Chemother. 2012;56(9):4856- 4861.
Oliva A, Gizzi F, Mascellino MT, Cipolla A, D’Abramo A, D’Agostino C, et al. Bactericidal and synergistic activity of double-carbapenem regimen for infections caused by carbapenemaseproducing Klebsiella pneumoniae. Clin Microbiol Infect. 2016;22(2):147-53.
Brennan-Krohn T, Kirby JE. Synergistic Combinations and Repurposed Antibiotics Active against the Pandrug-Resistant Klebsiella pneumoniae Nevada Strain. Antimicrob Agents Chemother. 2019;63(9):e01374-19.
Falagas ME, Voulgaris GL, Tryfinopoulou K, Giakkoupi P, Kyriakidou M, Vatopoulos A, et al. Synergistic activity of colistin with azidothymidine against colistin-resistant Klebsiella pneumoniae clinical isolates collected from inpatients in Greek hospitals. Int J Antimicrob Agents. 2019;53(6):855-8.
Morici P, Florio W, Rizzato C, Ghelardi E, Tavanti A, Rossolini GM, et al. Synergistic activity of synthetic N-terminal peptide of human lactoferrin in combination with various antibiotics against carbapenem-resistant Klebsiella pneumoniae strains. Eur J Clin Microbiol Infect Dis. 2017;36(10):1739-48.
Kwiatkowski P, Pruss A, Grygorcewicz B, Wojciuk B, Dolegowska B, Giedrys-Kalemba S, et al. Preliminary Study on the Antibacterial Activity of Essential Oils Alone and in Combination with Gentamicin Against ExtendedSpectrum beta-Lactamase-Producing and New Delhi Metallo-beta-Lactamase-1-Producing Klebsiella pneumoniae Isolates. Microb Drug Resist.2018;24(9):1368-75.
Ospina MAO, Pietralonga PAG, Schwarz DGG, Silva AJ, Paula SO, Moreira MAS. Effect of the inhibitors phenylalanine arginyl ß-naphthylamide (PAßN) and 1-(1-naphthylmethyl)-piperazine (NMP) on expression of genes in multidrug efflux systems of Escherichia coli isolates from bovine mastitis. Res Vet Sci. 2014;97(2):176-81.
Lloyd NA, Nazaret S, Barkay T. Genomefacilitated discovery of RND efflux pumpmediated resistance to cephalosporins in Vibrio spp. isolated from the mummichog fish gut. J Glob Antimicrob Resist. 2019;19:294-300.
Abdel-Halim H, Al Dajani A, Abdelhalim A, Abdelmalek S. The search of potential inhibitors of the AcrAB-TolC system of multidrug-resistant Escherichia coli: an in silico approach. Appl Microbiol Biotechnol. 2019;103(15):6309-18.
Wei S, Yang Y, Tian W, Liu M, Yin S, Li J. Synergistic Activity of Fluoroquinolones Combining with Artesunate Against MultidrugResistant Escherichia coli. Microb Drug Resist. 2020;26(1):81-8.
Kang HW, Woo GJ. Increase of multidrug efflux pump expression in fluoroquinolone-resistant Salmonella mutants induced by ciprofloxacin selective pressure. Res Vet Sci. 2014;97(2):182-6.
Pun M, Khazanov N, Galsurker O, Kerem Z, Senderowitz H, Yedidia I. Inhibition of AcrAB-TolC enhances antimicrobial activity of phytochemicals in Pectobacterium brasiliense. Front Plant Sci. 2023;14:1161702.
Li B, Yao Q, Pan XC, Wang N, Zhang R, Li J, et al. Artesunate enhances the antibacterial effect of {beta}-lactam antibiotics against Escherichia coli by increasing antibiotic accumulation via inhibition of the multidrug efflux pump system AcrAB-TolC. J Antimicrob Chemother. 2011;66(4):769-77.
Kim J, Shin B, Park C, Park W. Indole-Induced Activities of β-Lactamase and Efflux Pump Confer Ampicillin Resistance in Pseudomonas putida KT2440. Vol. 8, Frontiers in Microbiology. 2017. p. 433.
Bag A, Chattopadhyay RR. Efflux-pump inhibitory activity of a gallotannin from Terminalia chebula fruit against multidrug-resistant uropathogenic Escherichia coli. Nat Prod Res. 2014;28(16):1280- 1283.
Ranjan V, Mukherjee S, Thakur S, Gupta K, Chakraborty R. Ampicillin-Eating, CarbapenemResistant, Super-Superbug Pseudomonas sp. MR 02, Isolated from an Indian River, Mahananada, Has Exhaustive Repertoire of Genes to Combat All Classes of Antibiotics and Catabolize β-Lactams for Its Sustenance. SSRN Electronic Journal. 2019.
Price EDJ, Dassanayake RP, Bearson SMD. Increasing antimicrobial susceptibility of MDR Salmonella with the efflux pump inhibitor 1-(1-Naphthylmethyl)-piperazine. Biochem Biophys Res Commun. 2023;668:49-54.
Yoon EJ, Oh Y, Jeong SH. Development of Tigecycline Resistance in Carbapenemase-Producing Klebsiella pneumoniae Sequence Type 147 via AcrAB Overproduction Mediated by Replacement of the ramA Promoter. Ann Lab Med. 2020;40(1):15-20.
Maleki MH, Jalilian FA, Khayat H, Mohammadi M, Pourahmad F, Asadollahi K, et al. Detection of highly ciprofloxacin resistance acinetobacter baumannii isolated from patients with burn wound infections in presence and absence of efflux pump inhibitor. Maedica (Bucur). 2014;9(2):162-167.
Pulido IY, Mantilla JR, Valenzuela EM, Reguero MT, González EB. Distribución de genes codificadores de β-lactamasas de espectro extendido en aislamientos de Klebsiella pneumoniae de hospitales de Bogotá, D.C., Colombia. Biomédica. 2011;31(1):15-20.
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