TY - JOUR

T1 - The Effect of Shock Gentamicin Concentrations on the Formation of Resistance and Small Colony Variants in Staphylococcus aureus

T2 - Antibiotiki i Khimioterapiya

AU - Gostev, V.V.

AU - Kalinogorskaya, O.S.

AU - Sulian, O.S.

AU - Chulkova, P.S.

AU - Sopova, J.V.

AU - Velizhanina, M.E.

AU - Pleshkov, V.Y.

AU - Ageevets, V.A.

AU - Sidorenko, S.V.

N1 - Export Date: 4 March 2024 CODEN: ANKHE Адрес для корреспонденции: Gostev, V.V.; Pediatric Research and Clinical Center for Infectious Diseases under the Federal Medical Biological AgencyRussian Federation; эл. почта: guestvv11@gmail.com Пристатейные ссылки: Serio, A. W., Keepers, T., Andrews, L., Krause, K. M., Aminoglycoside Revival: Review of a Historically Important Class of Antimicrobials Undergoing Rejuvenation (2018) EcoSal Plus, 8 (1); Radlinski, L. C., Rowe, S. E., Brzozowski, R., Chemical Induction of Aminoglycoside Uptake Overcomes Antibiotic Tolerance and Resistance in Staphylococcus aureus (2019) Cell Chem Biol, 26 (10), pp. 1355-1364e4; Balwit, J. M., van Langevelde, P., Vann, J. M., Proctor, R. A., Gentamicin-resistant menadione and hemin auxotrophic Staphylococcus aureus persist within cultured endothelial cells (1994) J Infect Dis, 170 (4), pp. 1033-1037; Kriegeskorte, A., Lore, N. I., Bragonzi, A., Thymidine-dependent Staphylococcus aureus small-colony variants are induced by trimethoprimsulfamethoxazole (SXT) and have increased fitness during SXT challenge (2015) Antimicrob Agents Chemother, 59 (12), pp. 7265-7272; Kahl, B. C., Becker, K., Loffler, B., Clinical significance and pathogenesis of staphylococcal small colony variants in persistent infections (2016) Clin Microbiol Rev, 29 (2), pp. 401-427; Brown, N. M., Goodman, A. L., Horner, C., Treatment of methicillin-resistant Staphylococcus aureus (MRSA): updated guidelines from the UK (2021) JAC Antimicrob Resist, 3 (1), p. dlaa114; Davis, J. S., Van Hal, S., Tong, S. Y., Combination antibiotic treatment of serious methicillin-resistant Staphylococcus aureus infections (2015) Semin Respir Crit Care Med, 36 (1), pp. 3-16; Nicolau, D. P., Freeman, C. D., Belliveau, P. P., Experience with a once-daily aminoglycoside program administered to 2,184 adult patients (1995) Antimicrob Agents Chemother, 39 (3), pp. 650-655; Fridman, O., Goldberg, A., Ronin, I., Optimization of lag time underlies antibiotic tolerance in evolved bacterial populations (2014) Nature, 513 (7518), pp. 418-421; Sprouffske, K., Wagner, A., Growthcurver: an R package for obtaining interpretable metrics from microbial growth curves (2016) BMC Bioinformatics, 17, p. 172; Brown, J., Pirrung, M., McCue, L. A., FQC Dashboard: integrates FastQC results into a web-based, interactive, and extensible FASTQ quality control tool (2017) Bioinformatics, 33 (19), pp. 3137-3139; Bolger, A. M., Lohse, M., Usadel, B., Trimmomatic: a flexible trimmer for Illumina sequence data (2014) Bioinformatics, 30 (15), pp. 2114-2120; Bankevich, A., Nurk, S., Antipov, D., SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing (2012) J Comput Biol, 19 (5), pp. 455-477; Barrick, J. E., Colburn, G., Deatherage, D. E., Identifying structural variation in haploid microbial genomes from short-read resequencing data using breseq (2014) BMC Genomics, 15, p. 1039; Gostev, V. V., Sopova, Yu. V., Kalinogorskaya, O. S., Velizhanina, M. E., Lazareva, I. V., Starkova, P. S., Sidorenko, S. V., The Effects of shock vancomycin concentrations on the formation of heteroresistance (2020) Antibiotiki i Khimioter = Antibiotics and Chemotherapy, 65 (9–10), pp. 3-7. , https://doi.org/10.37489/0235-2990-2020-65-9-10-3-7, Гостев В. В., Сопова Ю. В., Калиногорская О. С. et al. Влияние шоковых концентраций ванкомицина на формирование гетерорезистентности Staphylococcus aureus. Антибиотики и химиотер. 2020; 65 (9–10): 3–7. https://doi.org/10.37489/0235-2990-2020-65-9-10-3-7. [(in Russian)]; Hodiamont, C. J., van den Broek, A. K., de Vroom, S. L., Clinical pharmacokinetics of gentamicin in various patient populations and consequences for optimal dosing for gram-negative infections: an updated review (2022) Clin Pharmacokinet, 61 (8), pp. 1075-1094; Khare, A., Tavazoie, S., Extreme Antibiotic persistence via heterogeneity-generating mutations targeting translation (2020) mSystems, 5 (1); Schaaff, F., Bierbaum, G., Baumert, N., Mutations are involved in emergence of aminoglycoside-induced small colony variants of Staphylococcus aureus (2003) Int J Med Microbiol, 293 (6), pp. 427-435; Tuchscherr, L., Kreis, C. A., Hoerr, V., Staphylococcus aureus develops increased resistance to antibiotics by forming dynamic small colony variants during chronic osteomyelitis (2016) J Antimicrob Chemother, 71 (2), pp. 438-448; Ibacache-Quiroga, C., Oliveros, J. C., Couce, A., Blazquez, J., Parallel evolution of high-level aminoglycoside resistance in Escherichia coli under low and high mutation supply rates (2018) Front Microbiol, 9, p. 427; Ng, J. M. L., Ngeow, Y. F., Saw, S. H., Mutations in atpG2 may confer resistance to gentamicin in Listeria monocytogenes (2022) J Med Microbiol, 71 (12); Vestergaard, M., Nohr-Meldgaard, K., Bojer, M. S., Inhibition of the ATP synthase eliminates the intrinsic resistance of Staphylococcus aureus towards polymyxins (2017) mBio, 8 (5); Liu, L., Beck, C., Nohr-Meldgaard, K., Inhibition of the ATP synthase sensitizes Staphylococcus aureus towards human antimicrobial peptides (2020) Sci Rep, 10 (1), p. 11391; Vestergaard, M., Leng, B., Haaber, J., Genome-Wide Identification of antimicrobial intrinsic resistance determinants in Staphylococcus aureus (2016) Front Microbiol, 7, p. 2018; Lobritz, M. A., Belenky, P., Porter, C. B., Antibiotic efficacy is linked to bacterial cellular respiration (2015) Proc Natl Acad Sci U S A, 112 (27), pp. 8173-8180; Rodriguez de Evgrafov, M. C., Faza, M., Asimakopoulos, K., Sommer, M. O. A., Systematic investigation of resistance evolution to common antibiotics reveals conserved collateral responses across common human pathogens (2020) Antimicrob Agents Chemother, 65 (1); Desai, J., Liu, Y. L., Wei, H., Structure, function, and inhibition of Staphylococcus aureus heptaprenyl diphosphate synthase (2016) ChemMedChem, 11 (17), pp. 1915-1923; Kang, K. M., Mishra, N. N., Park, K. T., Phenotypic and genotypic correlates of daptomycin-resistant methicillin-susceptible Staphylococcus aureus clinical isolates (2017) J Microbiol, 55 (2), pp. 153-159; Steed, M. E., Hall, A. D., Salimnia, H., Evaluation of daptomycin non-susceptible Staphylococcus aureus for stability, population profiles, mprf mutations, and daptomycin activity (2013) Infect Dis Ther, 2 (2), pp. 187-200; Jiang, J. H., Peleg, A. Y., Daptomycin-nonsusceptible Staphylococcus aureus: the role of combination therapy with daptomycin and gentamicin (2015) Genes (Basel), 6 (4), pp. 1256-1267

PY - 2023

Y1 - 2023

N2 - Gentamicin is one of the components of combination therapy for infective endocarditis caused by Staphylococcus aureus, including methicillin-resistant S.aureus (MRSA). The purpose of this study was to analyze the effect of ten 6-hour cycles of exposure to high concentrations (16 µg/ml) of gentamicin in vitro on the phenotype and genotype changes of aminoglycoside-susceptible S.aureus strains belonging to four sequence types (ST): ST5 (ATCC 29213), ST8, ST97, and ST22 (MRSA). After selection, an increase in the MIC of gentamicin to 8–64 µg/ml for all strains except ATCC 29213 was observed. One strain (SA0937) dissociated into three morphotypes, including a small colony variant (SCV). A derivative strain SA0937 variant with normal colony size was characterized by associated resistance to daptomycin due to the P314L mutation in MprF. Except for the SCV morphotype, there was no change in growth rate in response to the formation of resistance. After selection, the emergence of the ATCC 29213 strain tolerance was noted. It manifested by an increase in effective killing up to 14 hours in a 24-hour time-killing test with 16 µg/ml of antibiotic concentration. It was revealed that the ATCC 29213 strain has mutations in peptidyl-tRNA hydrolase (Pth). Deletions in the atpG gene, which is part of the ATP synthase complex, were found in three strains. Deletions and mutations in the menaquinone metabolism genes hepS, menA, and translation elongation factor G (fusA) were identified in the remaining derivative strains. Thus, the use of gentamicin is linked to possible rapid development of resistance and tolerance, which is not associated with the acquisition of aminoglycoside-modifying enzyme genes. Detection of SCV is associated with adverse clinical outcomes. It is important to consider the possibility of developing resistance to daptomycin due to gentamicin selection when using combination therapy. © 2023 Publishing House OKI. All rights reserved.

AB - Gentamicin is one of the components of combination therapy for infective endocarditis caused by Staphylococcus aureus, including methicillin-resistant S.aureus (MRSA). The purpose of this study was to analyze the effect of ten 6-hour cycles of exposure to high concentrations (16 µg/ml) of gentamicin in vitro on the phenotype and genotype changes of aminoglycoside-susceptible S.aureus strains belonging to four sequence types (ST): ST5 (ATCC 29213), ST8, ST97, and ST22 (MRSA). After selection, an increase in the MIC of gentamicin to 8–64 µg/ml for all strains except ATCC 29213 was observed. One strain (SA0937) dissociated into three morphotypes, including a small colony variant (SCV). A derivative strain SA0937 variant with normal colony size was characterized by associated resistance to daptomycin due to the P314L mutation in MprF. Except for the SCV morphotype, there was no change in growth rate in response to the formation of resistance. After selection, the emergence of the ATCC 29213 strain tolerance was noted. It manifested by an increase in effective killing up to 14 hours in a 24-hour time-killing test with 16 µg/ml of antibiotic concentration. It was revealed that the ATCC 29213 strain has mutations in peptidyl-tRNA hydrolase (Pth). Deletions in the atpG gene, which is part of the ATP synthase complex, were found in three strains. Deletions and mutations in the menaquinone metabolism genes hepS, menA, and translation elongation factor G (fusA) were identified in the remaining derivative strains. Thus, the use of gentamicin is linked to possible rapid development of resistance and tolerance, which is not associated with the acquisition of aminoglycoside-modifying enzyme genes. Detection of SCV is associated with adverse clinical outcomes. It is important to consider the possibility of developing resistance to daptomycin due to gentamicin selection when using combination therapy. © 2023 Publishing House OKI. All rights reserved.

KW - gentamicin

KW - menaquinone biosynthesis

KW - mutations

KW - resistance

KW - selection

KW - small colony variants

KW - Staphylococcus aureus

U2 - 10.37489/0235-2990-2023-68-9-10-25-33

DO - 10.37489/0235-2990-2023-68-9-10-25-33

M3 - статья

VL - 68

SP - 25

EP - 33

JO - АНТИБИОТИКИ И ХИМИОТЕРАПИЯ

JF - АНТИБИОТИКИ И ХИМИОТЕРАПИЯ

SN - 0235-2990

IS - 9-10

ER -