Heterogeneous subpopulations in Escherichia coli strains acquire adaptive resistance to imipenem treatment through rapid transcriptional regulation
IntroductionHeteroresistance is a well-known phenomenon contributing to treatment failure in bacterial infections. Previous research has traditionally linked it to genetic mechanisms, emphasizing fixed subpopulations with specific resistance mutations. Recent studies appreciated that bacterial subpo...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| author | YunTao Luo Rong Xu Bo Yuan WeiHua Yang YunHeng Zhou Yuan Tian QingZhong Wang |
| author_facet | YunTao Luo Rong Xu Bo Yuan WeiHua Yang YunHeng Zhou Yuan Tian QingZhong Wang |
| author_sort | YunTao Luo |
| collection | DOAJ |
| description | IntroductionHeteroresistance is a well-known phenomenon contributing to treatment failure in bacterial infections. Previous research has traditionally linked it to genetic mechanisms, emphasizing fixed subpopulations with specific resistance mutations. Recent studies appreciated that bacterial subpopulations may not be fixed and independent, but rather dynamically changing. Heteroresistance mechanisms are likely more intricate than mere genetic predisposition alone.MethodsOur study investigated the role of non-genetically encoded mechanisms in early stages of occurrence and development of heteroresistance through transcriptome analysis and molecular biology experiments.ResultsWe identified a clinical Escherichia coli strain that, despite no prior antibiotic treatment, still exhibited imipenem heteroresistance. We found that these heteroresistance populations can rapidly acquire adaptive capability for imipenem-resistance through an active and dynamic gene regulatory process. At their highly resistant stage, the transcriptome is primarily characterized by enhanced expression of related genes in exopolysaccharide and peptidoglycan biosynthesis (wcaE, wcaF, mrcB, murA, etc), leading to critical alterations in bacterial intracellular and intercellular structure, including maintaining the integrity of the outer cell membrane and the promotion of biofilm formation. Conversely, in antibiotics-free conditions, these highly imipenem-resistant subpopulations can revert to an imipenem-sensitive state, accompanied by reversed gene expression. Additionally, we discovered that extremely low-level antibiotic exposure can regenerate heteroresistance populations, accompanied by similar pattern of gene expression.DiscussionOverall, our study revealed non-genetic mechanisms that enable bacterial strains to acquire adaptive imipenem-resistance rapidly. Moreover, preventing hospital-acquired infections should focus not only on eliminating residual bacteria but also on removing residual antibiotics in clinical settings. |
| format | Article |
| id | doaj-art-567fa0b5cd6e4d2ab9f1daa2f74d946f |
| institution | DOAJ |
| issn | 2235-2988 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj-art-567fa0b5cd6e4d2ab9f1daa2f74d946f2025-08-20T03:21:47ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882025-05-011510.3389/fcimb.2025.15633161563316Heterogeneous subpopulations in Escherichia coli strains acquire adaptive resistance to imipenem treatment through rapid transcriptional regulationYunTao Luo0Rong Xu1Bo Yuan2WeiHua Yang3YunHeng Zhou4Yuan Tian5QingZhong Wang6Clinical Microbiology Laboratory, Shanghai Center for Clinical Laboratory, Shanghai, ChinaClinical Microbiology Laboratory, Shanghai Center for Clinical Laboratory, Shanghai, ChinaOutpatient Department of Clinical Laboratory, Shanghai Tenth People’s Hospital, Shanghai, ChinaDepartment of Clinical Laboratory, Zhabei Central Hospital of Jing’an District, Shanghai, ChinaDepartment of Clinical Laboratory, Zhabei Central Hospital of Jing’an District, Shanghai, ChinaShanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, ChinaClinical Microbiology Laboratory, Shanghai Center for Clinical Laboratory, Shanghai, ChinaIntroductionHeteroresistance is a well-known phenomenon contributing to treatment failure in bacterial infections. Previous research has traditionally linked it to genetic mechanisms, emphasizing fixed subpopulations with specific resistance mutations. Recent studies appreciated that bacterial subpopulations may not be fixed and independent, but rather dynamically changing. Heteroresistance mechanisms are likely more intricate than mere genetic predisposition alone.MethodsOur study investigated the role of non-genetically encoded mechanisms in early stages of occurrence and development of heteroresistance through transcriptome analysis and molecular biology experiments.ResultsWe identified a clinical Escherichia coli strain that, despite no prior antibiotic treatment, still exhibited imipenem heteroresistance. We found that these heteroresistance populations can rapidly acquire adaptive capability for imipenem-resistance through an active and dynamic gene regulatory process. At their highly resistant stage, the transcriptome is primarily characterized by enhanced expression of related genes in exopolysaccharide and peptidoglycan biosynthesis (wcaE, wcaF, mrcB, murA, etc), leading to critical alterations in bacterial intracellular and intercellular structure, including maintaining the integrity of the outer cell membrane and the promotion of biofilm formation. Conversely, in antibiotics-free conditions, these highly imipenem-resistant subpopulations can revert to an imipenem-sensitive state, accompanied by reversed gene expression. Additionally, we discovered that extremely low-level antibiotic exposure can regenerate heteroresistance populations, accompanied by similar pattern of gene expression.DiscussionOverall, our study revealed non-genetic mechanisms that enable bacterial strains to acquire adaptive imipenem-resistance rapidly. Moreover, preventing hospital-acquired infections should focus not only on eliminating residual bacteria but also on removing residual antibiotics in clinical settings.https://www.frontiersin.org/articles/10.3389/fcimb.2025.1563316/fullheteroresistancetranscriptional regulationEscherichia colinon-genetic mechanismfitness cost |
| spellingShingle | YunTao Luo Rong Xu Bo Yuan WeiHua Yang YunHeng Zhou Yuan Tian QingZhong Wang Heterogeneous subpopulations in Escherichia coli strains acquire adaptive resistance to imipenem treatment through rapid transcriptional regulation Frontiers in Cellular and Infection Microbiology heteroresistance transcriptional regulation Escherichia coli non-genetic mechanism fitness cost |
| title | Heterogeneous subpopulations in Escherichia coli strains acquire adaptive resistance to imipenem treatment through rapid transcriptional regulation |
| title_full | Heterogeneous subpopulations in Escherichia coli strains acquire adaptive resistance to imipenem treatment through rapid transcriptional regulation |
| title_fullStr | Heterogeneous subpopulations in Escherichia coli strains acquire adaptive resistance to imipenem treatment through rapid transcriptional regulation |
| title_full_unstemmed | Heterogeneous subpopulations in Escherichia coli strains acquire adaptive resistance to imipenem treatment through rapid transcriptional regulation |
| title_short | Heterogeneous subpopulations in Escherichia coli strains acquire adaptive resistance to imipenem treatment through rapid transcriptional regulation |
| title_sort | heterogeneous subpopulations in escherichia coli strains acquire adaptive resistance to imipenem treatment through rapid transcriptional regulation |
| topic | heteroresistance transcriptional regulation Escherichia coli non-genetic mechanism fitness cost |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2025.1563316/full |
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