{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:48:05Z","timestamp":1790754485812,"version":"4.1.0"},"reference-count":83,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,6,17]],"date-time":"2023-06-17T00:00:00Z","timestamp":1686960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000082","name":"Cystic Fibrosis Canada","doi-asserted-by":"publisher","award":["3010"],"award-info":[{"award-number":["3010"]}],"id":[{"id":"10.13039\/501100000082","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000082","name":"Cystic Fibrosis Canada","doi-asserted-by":"publisher","award":["2020-04811"],"award-info":[{"award-number":["2020-04811"]}],"id":[{"id":"10.13039\/501100000082","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Sciences and Engineering Research Council of Canada","award":["3010"],"award-info":[{"award-number":["3010"]}]},{"name":"Natural Sciences and Engineering Research Council of Canada","award":["2020-04811"],"award-info":[{"award-number":["2020-04811"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Prototypic Staphylococcus aureus and their small-colony variants (SCVs) are predominant in cystic fibrosis (CF), but the interdependence of these phenotypes is poorly understood. We characterized S. aureus isolates from adult CF patients over several years. Of 18 S. aureus-positive patients (58%), 13 (72%) were positive for SCVs. Characterization included genotyping, SCCmec types, auxotrophy, biofilm production, antibiotic susceptibilities and tolerance, and resistance acquisition rates. Whole-genome sequencing revealed that several patients were colonized with prototypical and SCV-related clones. Some clonal pairs showed acquisition of aminoglycoside resistance that was not explained by aminoglycoside-modifying enzymes, suggesting a mutation-based process. The characteristics of SCVs that could play a role in resistance acquisition were thus investigated further. For instance, SCV isolates produced more biofilm (p &lt; 0.05) and showed a higher survival rate upon exposure to ciprofloxacin and vancomycin compared to their prototypic associated clones. SCVs also developed spontaneous rifampicin resistance mutations at a higher frequency. Accordingly, a laboratory-derived SCV (\u0394hemB) acquired resistance to ciprofloxacin and gentamicin faster than its parent counterpart after serial passages in the presence of sub-inhibitory concentrations of antibiotics. These results suggest a role for SCVs in the establishment of persistent antibiotic-resistant clones in adult CF patients.<\/jats:p>","DOI":"10.3390\/antibiotics12061069","type":"journal-article","created":{"date-parts":[[2023,6,19]],"date-time":"2023-06-19T01:31:14Z","timestamp":1687138274000},"page":"1069","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Staphylococcus aureus Small-Colony Variants from Airways of Adult Cystic Fibrosis Patients as Precursors of Adaptive Antibiotic-Resistant Mutations"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0222-6935","authenticated-orcid":false,"given":"Guillaume","family":"Millette","sequence":"first","affiliation":[{"name":"D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Lalonde","family":"S\u00e9guin","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Isabelle","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Chamberland","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Fran\u00e7ois","family":"Lucier","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Rodrigue","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 M.","family":"Cantin","sequence":"additional","affiliation":[{"name":"Service de Pneumologie, D\u00e9partement de M\u00e9decine, Facult\u00e9 de M\u00e9decine et des Sciences de la Sant\u00e9, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Malouin","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,17]]},"reference":[{"key":"ref_1","unstructured":"(2023, May 01). The Canadian Cystic Fibrosis Registry Annual Report. In Cystic Fibrosis Canada [Internet]. Available online: www.cysticfibrosis.ca."},{"key":"ref_2","unstructured":"(2023, May 01). 2021 Annual Data Report\u2014Cystic Fibrosis Foundation Patient Registry. Available online: https:\/\/www.cff.org\/medical-professionals\/patient-registry."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1002\/ppul.20294","article-title":"Lower airway inflammation in infants with cystic fibrosis detected by newborn screening","volume":"40","author":"Armstrong","year":"2005","journal-title":"Pediatr. Pulmonol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.jpeds.2008.08.001","article-title":"Inhaled Tobramycin in Young Children Study Group; Cystic Fibrosis Foundation Therapeutics Development Network. Impact of Pseudomonas and Staphylococcus infection on inflammation and clinical status in young children with cystic fibrosis","volume":"154","author":"Sagel","year":"2009","journal-title":"J. Pediatr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.jcf.2022.08.001","article-title":"Antibiotics and outcomes of CF pulmonary exacerbations in children infected with MRSA and Pseudomonas aeruginosa","volume":"22","author":"Cogen","year":"2022","journal-title":"J. Cyst. Fibros."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ahlgren, H.G., Benedetti, A., Landry, J.S., Bernier, J., Matouk, E., Radzioch, D., Lands, L.C., Rousseau, S., and Nguyen, D. (2015). Clinical outcomes associated with Staphylococcus aureus and Pseudomonas aeruginosa airway infections in adult cystic fibrosis patients. BMC Pulm. Med., 15.","DOI":"10.1186\/s12890-015-0062-7"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.ijmm.2018.02.003","article-title":"Staphylococcus aureus in the airways of cystic fibrosis patients\u2014A retrospective long-term study","volume":"308","author":"Schwerdt","year":"2018","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1093\/cid\/cit270","article-title":"Staphylococcus aureus small-colony variants are independently associated with worse lung disease in children with cystic fibrosis","volume":"57","author":"Wolter","year":"2013","journal-title":"Clin. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Junge, S., G\u00f6rlich, D., den Reijer, M., Wiedemann, B., T\u00fcmmler, B., Ellemunter, H., D\u00fcbbers, A., K\u00fcster, P., Ballmann, M., and Koerner-Rettberg, C. (2016). Factors Associated with Worse Lung Function in Cystic Fibrosis Patients with Persistent Staphylococcus aureus. Omri A, editor. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166220"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1016\/S2213-2600(19)30365-0","article-title":"Prevalence and clinical associations of Staphylococcus aureus small-colony variant respiratory infection in children with cystic fibrosis (SCVSA): A multicentre, observational study","volume":"7","author":"Wolter","year":"2019","journal-title":"Lancet Respir. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.ajic.2015.10.015","article-title":"Clinical characteristics and epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in children with cystic fibrosis from a center with a high MRSA prevalence","volume":"44","author":"Harik","year":"2016","journal-title":"Am. J. Infect. Control."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1001\/jama.2010.791","article-title":"Association between respiratory tract methicillin-resistant Staphylococcus aureus and survival in cystic fibrosis","volume":"303","author":"Dasenbrook","year":"2010","journal-title":"JAMA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.ijmm.2010.08.002","article-title":"Impact of Staphylococcus aureus on the pathogenesis of chronic cystic fibrosis lung disease","volume":"300","author":"Kahl","year":"2010","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1128\/CMR.00069-15","article-title":"Clinical Significance and Pathogenesis of Staphylococcal Small Colony Variants in Persistent Infections","volume":"29","author":"Kahl","year":"2016","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1128\/AAC.18.5.722","article-title":"Gentamicin uptake in wild-type and aminoglycoside-resistant small-colony mutants of Staphylococcus aureus","volume":"18","author":"Miller","year":"1980","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/nrmicro1384","article-title":"Small colony variants: A pathogenic form of bacteria that facilitates persistent and recurrent infections","volume":"4","author":"Proctor","year":"2006","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.micpath.2009.10.003","article-title":"A role for sigma factor B in the emergence of Staphylococcus aureus small-colony variants and elevated biofilm production resulting from an exposure to aminoglycosides","volume":"48","author":"Mitchell","year":"2010","journal-title":"Microb. Pathog."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1111\/j.1365-2958.2008.06511.x","article-title":"Staphylococcus aureus SigB activity promotes a strong fibronectin-bacterium interaction which may sustain host tissue colonization by small-colony variants isolated from cystic fibrosis patients","volume":"70","author":"Mitchell","year":"2008","journal-title":"Mol. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1128\/JB.188.1.64-76.2006","article-title":"Transcription of virulence factors in Staphylococcus aureus small-colony variants isolated from cystic fibrosis patients is influenced by SigB","volume":"188","author":"Moisan","year":"2006","journal-title":"J. Bacteriol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1093\/infdis\/170.4.1033","article-title":"Gentamicin-resistant menadione and hemin auxotrophic Staphylococcus aureus persist within cultured endothelial cells","volume":"170","author":"Balwit","year":"1994","journal-title":"J. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.3389\/fmicb.2020.01028","article-title":"Persistence of Staphylococcus aureus: Multiple Metabolic Pathways Impact the Expression of Virulence Factors in Small-Colony Variants (SCVs)","volume":"11","author":"Tuchscherr","year":"2020","journal-title":"Front. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/microbiolspec.GPP3-0069-2019","article-title":"Respiration and Small Colony Variants of Staphylococcus aureus","volume":"7","author":"Proctor","year":"2019","journal-title":"Microbiol. Spectr."},{"key":"ref_23","first-page":"CD001912","article-title":"Prophylactic anti-staphylococcal antibiotics for cystic fibrosis","volume":"2020","author":"Rosenfeld","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_24","first-page":"CD009650","article-title":"Interventions for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis","volume":"2018","author":"Lo","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S2213-2600(19)30337-6","article-title":"The Lancet Respiratory Medicine Commission on the Future of Care of Cystic Fibrosis","volume":"8","author":"Bell","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1128\/microbiolspec.GPP3-0023-2018","article-title":"Staphylococcal Biofilms","volume":"6","author":"Otto","year":"2018","journal-title":"Microbiol. Spectr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1038\/jid.2014.176","article-title":"Decreased Susceptibility of Staphylococcus aureus Small-Colony Variants toward Human Antimicrobial Peptides","volume":"134","author":"Becker","year":"2014","journal-title":"J. Invest. Dermatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nrmicro.2017.42","article-title":"Persistent bacterial infections and persister cells","volume":"15","author":"Fisher","year":"2017","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1038\/s41396-019-0344-9","article-title":"Bacterial persistence promotes the evolution of antibiotic resistance by increasing survival and mutation rates","volume":"13","author":"Windels","year":"2019","journal-title":"ISME J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7265","DOI":"10.1128\/AAC.00742-15","article-title":"Thymidine-Dependent Staphylococcus aureus Small-Colony Variants Are Induced by Trimethoprim-Sulfamethoxazole (SXT) and Have Increased Fitness during SXT Challenge","volume":"59","author":"Kriegeskorte","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Vestergaard, M., Paulander, W., and Ingmer, H. (2015). Activation of the SOS response increases the frequency of small colony variants. BMC Res. Notes., 8.","DOI":"10.1186\/s13104-015-1735-2"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"19890","DOI":"10.1073\/pnas.0606756104","article-title":"Selection for Staphylococcus aureus small-colony variants due to growth in the presence of Pseudomonas aeruginosa","volume":"103","author":"Hoffman","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Mitchell, G., S\u00e9guin, D.L., Asselin, A.-E., D\u00e9ziel, E., Cantin, A.M., Frost, E.H., Michaud, S., and Malouin, F. (2010). Staphylococcus aureus sigma B-dependent emergence of small-colony variants and biofilm production following exposure to Pseudomonas aeruginosa 4-hydroxy-2-heptylquinoline-N-oxide. BMC Microbiol., 10.","DOI":"10.1186\/1471-2180-10-33"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1042\/bj0630130","article-title":"Inhibition of cytochrome systems of heart muscle and certain bacteria by the antagonists of dihydrostreptomycin: 2-alkyl-4-hydroxyquinoline N-oxides","volume":"63","author":"Lightbown","year":"1956","journal-title":"Biochem. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1093\/infdis\/173.3.739","article-title":"Staphylococcus aureus small colony variants are induced by the endothelial cell intracellular milieu","volume":"173","author":"Vesga","year":"1996","journal-title":"J. Infect. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.micinf.2014.09.009","article-title":"The induction of Staphylococcus aureus biofilm formation or Small Colony Variants is a strain-specific response to host-generated chemical stresses","volume":"17","author":"Bui","year":"2015","journal-title":"Microbes Infect."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Gao, W., Chua, K., Davies, J.K., Newton, H.J., Seemann, T., Harrison, P., Holmes, N.E., Rhee, H.-W., Hong, J.-I., and Hartland, E. (2010). Two novel point mutations in clinical Staphylococcus aureus reduce linezolid susceptibility and switch on the stringent response to promote persistent infection. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1000944"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1128\/IAI.03016-14","article-title":"Staphylococcus aureus adapts to oxidative stress by producing H2O2-resistant small-colony variants via the SOS response","volume":"83","author":"Painter","year":"2015","journal-title":"Infect. Immun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1128\/mr.51.4.439-457.1987","article-title":"Bacterial uptake of aminoglycoside antibiotics","volume":"51","author":"Taber","year":"1987","journal-title":"Microbiol. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e0035821","DOI":"10.1128\/mSphere.00358-21","article-title":"Association of Diverse Staphylococcus aureus Populations with Pseudomonas aeruginosa Coinfection and Inflammation in Cystic Fibrosis Airway Infection","volume":"6","author":"Wieneke","year":"2021","journal-title":"mSphere."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/mBio.00735-20","article-title":"Genotypic and phenotypic diversity of Staphylococcus aureus isolates from cystic fibrosis patient lung infections and their interactions with Pseudomonas aeruginosa","volume":"11","author":"Bernardy","year":"2020","journal-title":"MBio"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Kittinger, C., Toplitsch, D., Folli, B., Landgraf, L.M., and Zarfel, G. (2019). Phenotypic Stability of Staphylococcus aureus Small Colony Variants (SCV) Isolates from Cystic Fibrosis (CF) Patients. Int. J. Environ. Res. Public. Health, 16.","DOI":"10.3390\/ijerph16111940"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e00553-19","DOI":"10.1128\/mSphere.00553-19","article-title":"Quorum Sensing, Virulence, and Antibiotic Resistance of USA100 Methicillin-Resistant Staphylococcus aureus Isolates","volume":"4","author":"Grundstad","year":"2019","journal-title":"mSphere"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e00019-18","DOI":"10.1128\/CMR.00019-18","article-title":"Epidemiology, Biology, and Impact of Clonal Pseudomonas aeruginosa Infections in Cystic Fibrosis. Clinical microbiology reviews","volume":"31","author":"Parkins","year":"2018","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_45","unstructured":"Thornton, C.S., and Parkins, M.D. (2023). Seminars in Respiratory and Critical Care Medicine, Thieme Medical Publishers, Inc."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Biggs, S.L., Jennison, A.V., Bergh, H., Graham, R., Nimmo, G., and Whiley, D. (2022). Limited evidence of patient-to-patient transmission of Staphylococcus aureus strains between children with cystic fibrosis, Queensland, Australia. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0275256"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"230","DOI":"10.3389\/fmicb.2020.00230","article-title":"Antibiotic Treatment and Age Are Associated with Staphylococcus aureus Carriage Profiles during Persistence in the Airways of Cystic Fibrosis Patients","volume":"11","author":"Westphal","year":"2020","journal-title":"Front. Microbiol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Rumpf, C., Lange, J., Schwartbeck, B., and Kahl, B.C. (2021). Staphylococcus aureus and cystic fibrosis\u2014A close relationship. What can we learn from sequencing studies?. Pathogens, 10.","DOI":"10.3390\/pathogens10091177"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"aaf4268","DOI":"10.1126\/science.aaf4268","article-title":"Mechanisms of bacterial persistence during stress and antibiotic exposure","volume":"354","author":"Harms","year":"2016","journal-title":"Science"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1128\/CMR.00042-09","article-title":"Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: Resistance mechanisms, laboratory detection, and clinical implications","volume":"23","author":"Howden","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0065018","article-title":"SigB Is a Dominant Regulator of Virulence in Staphylococcus aureus Small-Colony Variants","volume":"8","author":"Mitchell","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1006\/bbrc.2001.5774","article-title":"Overexpression of Sigma Factor B, Urges Staphylococcus aureus to Thicken the Cell Wall and to Resist \u03b2-Lactams","volume":"288","author":"Morikawa","year":"2001","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Chen, H.Y., Chen, C.C., Fang, C.S., Hsieh, Y.T., Lin, M.H., and Shu, J.C. (2011). Vancomycin activates \u03c3 B in vancomycin-resistant Staphylococcus aureus resulting in the enhancement of cytotoxicity. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024472"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"S26","DOI":"10.1016\/j.injury.2006.04.006","article-title":"The small colony variant (SCV) concept\u2014The role of staphylococcal SCVs in persistent infections","volume":"37","author":"Peters","year":"2006","journal-title":"Injury."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.3389\/fmicb.2018.01863","article-title":"The energy-coupling factor transporter module EcfAA\u2019T, a novel candidate for the genetic basis of fatty acid-auxotrophic small-colony variants of Staphylococcus aureus","volume":"9","author":"Schleimer","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"475","DOI":"10.4103\/0976-9668.160046","article-title":"Breast abscess in a case of duct atresia caused by CO2-auxotrophic small colony variants of Staphylococcus aureus: Case report and review of literature","volume":"6","author":"Bhattacharyya","year":"2015","journal-title":"J. Nat. Sci. Biol. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.1128\/JCM.00520-10","article-title":"Clinical and molecular characteristics of infections with CO2-dependent small-colony variants of Staphylococcus aureus","volume":"48","author":"Acosta","year":"2010","journal-title":"J. Clin. Microbiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3876","DOI":"10.1038\/s41598-018-21925-6","article-title":"Fatty Acid Supplementation Reverses the Small Colony Variant Phenotype in Triclosan-Adapted Staphylococcus aureus: Genetic, Proteomic and Phenotypic Analyses","volume":"8","author":"Bazaid","year":"2018","journal-title":"Sci Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1128\/IAI.01075-07","article-title":"Influence of dTMP on the phenotypic appearance and intracellular persistence of Staphylococcus aureus","volume":"76","author":"Zander","year":"2008","journal-title":"Infect. Immun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.ijmm.2010.08.009","article-title":"Mutators in cystic fibrosis chronic lung infection: Prevalence, mechanisms, and consequences for antimicrobial therapy","volume":"300","author":"Oliver","year":"2010","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"10453","DOI":"10.1074\/jbc.M111.318121","article-title":"Structural insights into methyltransferase KsgA function in 30S ribosomal subunit biogenesis","volume":"287","author":"Boehringer","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1093\/nar\/gkp057","article-title":"KsgA, a 16S rRNA adenine methyltransferase, has a novel DNA glycosylase\/AP lyase activity to prevent mutations in Escherichia coli","volume":"37","author":"Morinaga","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1128\/AAC.00873-08","article-title":"Inactivation of KsgA, a 16S rRNA methyltransferase, causes vigorous emergence of mutants with high-level kasugamycin resistance","volume":"53","author":"Ochi","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Lama, A., Pan\u00e9-Farr\u00e9, J., Chon, T., Wiersma, A.M., Sit, C.S., Vederas, J.C., Hecker, M., and Nakano, M.M. (2012). Response of methicillin-resistant Staphylococcus aureus to amicoumacin a. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034037"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/AAC.00853-18","article-title":"Studies on aminoglycoside susceptibility identify a novel function of KsgA to secure translational fidelity during antibiotic stress","volume":"62","author":"Zou","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"5414","DOI":"10.1038\/sj.emboj.7601393","article-title":"A novel adaptation of aldolase regulates virulence in Streptococcus pyogenes","volume":"25","author":"Loughman","year":"2006","journal-title":"EMBO J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1111\/j.1365-2958.2007.05663.x","article-title":"Comparative functional analysis of the lac operons in Streptococcus pyogenes","volume":"64","author":"Loughman","year":"2007","journal-title":"Mol. Microbiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.febslet.2010.12.038","article-title":"Crystal structures of LacD from Staphylococcus aureus and LacD.1 from Streptococcus pyogenes: Insights into substrate specificity and virulence gene regulation","volume":"585","author":"Lee","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1002\/ppul.26261","article-title":"Impact of elexacaftor-tezacaftor-ivacaftor on bacterial colonization and inflammatory responses in cystic fibrosis","volume":"58","author":"Sheikh","year":"2023","journal-title":"Pediatr. Pulmonol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.femsim.2003.12.007","article-title":"Persistence of a Staphylococcus aureus small-colony variant under antibiotic pressure in vivo","volume":"41","author":"Brouillette","year":"2004","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1128\/CMR.4.1.35","article-title":"Microbiology of airway disease in patients with cystic fibrosis","volume":"4","author":"Gilligan","year":"1991","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1128\/jcm.11.6.552-557.1980","article-title":"Bacteriology of sputum in cystic fibrosis: Evaluation of dithiothreitol as a mucolytic agent","volume":"11","author":"Hammerschlag","year":"1980","journal-title":"J. Clin. Microbiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1164\/rccm.200304-505SO","article-title":"Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis","volume":"168","author":"Gibson","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1093\/labmed\/15.4.258","article-title":"Bacteriologic plate media: Review of mechanisms of action","volume":"15","author":"Estevez","year":"1984","journal-title":"Lab. Med."},{"key":"ref_75","unstructured":"Murray, C. (1999). Manual of Clinical Microbiology, American Society for Microbiology. [7th ed.]."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.ijfoodmicro.2007.02.013","article-title":"Novel multiplex PCR for the detection of the Staphylococcus aureus superantigen and its application to raw meat isolates in Korea","volume":"117","author":"Hwang","year":"2007","journal-title":"Int. J. Food Microbiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1128\/jcm.29.10.2240-2244.1991","article-title":"Identification of methicillin-resistant strains of staphylococci by polymerase chain reaction","volume":"29","author":"Murakami","year":"1991","journal-title":"J. Clin. Microbiol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1128\/JCM.41.4.1801-1804.2003","article-title":"New Method for Typing Staphylococcus aureus Strains: Multiple-Locus Variable-Number Tandem Repeat Analysis of Polymorphism and Genetic Relationships of Clinical Isolates","volume":"41","author":"Sabat","year":"2003","journal-title":"J. Clin. Microbiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4060","DOI":"10.1128\/JCM.40.11.4060-4067.2002","article-title":"Analysis of the genetic variability of genes encoding the RNA III-activating components Agr and TRAP in a population of Staphylococcus aureus strains isolated from cows with mastitis","volume":"40","author":"Gilot","year":"2002","journal-title":"J. Clin. Microbiol."},{"key":"ref_80","unstructured":"CLSI Clinical and Laboratory Standards Institute (2018). Performance Standards for Antimicrobial Susceptibility Testing, Clinical and Laboratory Standards Institute. Twenty-Second Informational Supplement; CLSI document M100-S22."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"5026","DOI":"10.1128\/JCM.43.10.5026-5033.2005","article-title":"Novel multiplex PCR assay for characterization and concomitant subtyping of staphylococcal cassette chromosome mec types I to V in methicillin-resistant Staphylococcus aureus","volume":"43","author":"Zhang","year":"2005","journal-title":"J. Clin. Microbiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1093\/jac\/dkr510","article-title":"Tomatidine acts in synergy with aminoglycoside antibiotics against multiresistant Staphylococcus aureus and prevents virulence gene expression","volume":"67","author":"Mitchell","year":"2012","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"7458","DOI":"10.1128\/AAC.01711-15","article-title":"Bactericidal effect of tomatidine-tobramycin combination against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa is enhanced by interspecific small-molecule interactions","volume":"59","author":"Boulanger","year":"2015","journal-title":"Antimicrob. Agents Chemother."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/6\/1069\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:55:37Z","timestamp":1760126137000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/6\/1069"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,17]]},"references-count":83,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["antibiotics12061069"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics12061069","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,17]]}}}