Clinical characteristics, molecular epidemiology and mechanisms of colistin heteroresistance in Enterobacter cloacae complex
IntroductionColistin has emerged as the last resort for treating multidrug-resistant Enterobacter cloacae complex (ECC) infections. The primary purposes of this study were to demonstrate the presence of colistin heteroresistance in ECC and to further investigate their clinical characteristics, molec...
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Frontiers Media S.A.
2025-03-01
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| author | Chunli Wei Jiming Wu Jisheng Zhang Youtao Liang Kaixin Yu Kaixin Yu Mingjing Liao Xushan Liang Jianmin Wang Wenzhang Long Jin Wang Shijian Chen Yang Yang Xue Gong Jie Li Xiaoli Zhang |
| author_facet | Chunli Wei Jiming Wu Jisheng Zhang Youtao Liang Kaixin Yu Kaixin Yu Mingjing Liao Xushan Liang Jianmin Wang Wenzhang Long Jin Wang Shijian Chen Yang Yang Xue Gong Jie Li Xiaoli Zhang |
| author_sort | Chunli Wei |
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| description | IntroductionColistin has emerged as the last resort for treating multidrug-resistant Enterobacter cloacae complex (ECC) infections. The primary purposes of this study were to demonstrate the presence of colistin heteroresistance in ECC and to further investigate their clinical characteristics, molecular epidemiology and mechanisms.MethodsPopulation analysis profiles (PAP) were performed to confirm the heteroresistance phenotype. Average nucleotide identity (ANI) was determined to classify ECC species. Phylogenetic analysis based on core genome single nucleotide polymorphisms (cg-SNPs), multilocus sequence typing (MLST) and core genome MLST (cg-MLST). Risk factors and clinical outcomes of infections were analyzed through a retrospective case-control study. Potential mechanisms of colistin heteroresistance were evaluated using polymerase chain reaction (PCR), efflux pump inhibition assays and reverse transcription quantitative PCR (RT-qPCR).ResultsA high proportion (24.4%) of the non-resistant strains were colistin-heteroresistant isolates. Among the several ECC species, Enterobacter kobei had the largest percentage (29.4%) of colistin-heteroresistant isolates, followed by Enterobacter hormaechei (20.5%) and Enterobacter bugandensis (20.0%). Notably, only one strain (0.8%; 1/132) of Enterobacter hormaechei was fully resistant to colistin. Different ECC species showed varying heteroresistance levels: Enterobacter roggenkampii, Enterobacter kobei, Enterobacter asburiae and Enterobacter bugandensis displayed high heteroresistance levels (MIC ≥ 128 mg/L). 75% of all ST116 and ST56 strains were heteroresistant to colistin. The infection of ST116 and ST56 strains as well as exposure to cephalosporin antibiotics were independent risk factors for colistin-heteroresistant ECC infections. Mechanistic analysis revealed that heteroresistance strongly correlated with the overexpression of arnA, regulated by the PhoPQ two-component system (TCS). Notably, mgrB had minimal impact. AcrAB-TolC efflux pump genes showed unsynchronized expression; High acrB expression was strongly associated with colistin heteroresistance, while acrA and tolC were not.DiscussionColistin heteroresistance showed species-dependent variations in levels and prevalence rates. The colistin-heteroresistant mechanisms were complex, involving coordinated regulation of multiple genes. These results highlighted the need for tailored antimicrobial stewardship. In addition, the development of direct, reliable and rapid clinical methods for detecting heteroresistance is essential for improving infection management and prevention. |
| format | Article |
| id | doaj-art-c5e7191eb12c4c43a68caa8fafe1de5c |
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| publishDate | 2025-03-01 |
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| spelling | doaj-art-c5e7191eb12c4c43a68caa8fafe1de5c2025-08-20T03:16:18ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882025-03-011510.3389/fcimb.2025.15360581536058Clinical characteristics, molecular epidemiology and mechanisms of colistin heteroresistance in Enterobacter cloacae complexChunli Wei0Jiming Wu1Jisheng Zhang2Youtao Liang3Kaixin Yu4Kaixin Yu5Mingjing Liao6Xushan Liang7Jianmin Wang8Wenzhang Long9Jin Wang10Shijian Chen11Yang Yang12Xue Gong13Jie Li14Xiaoli Zhang15Department of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Pathogenic Biology, Basic Medicine of Jiamusi University, Jiamusi, ChinaDepartment of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Microbiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, ChinaIntroductionColistin has emerged as the last resort for treating multidrug-resistant Enterobacter cloacae complex (ECC) infections. The primary purposes of this study were to demonstrate the presence of colistin heteroresistance in ECC and to further investigate their clinical characteristics, molecular epidemiology and mechanisms.MethodsPopulation analysis profiles (PAP) were performed to confirm the heteroresistance phenotype. Average nucleotide identity (ANI) was determined to classify ECC species. Phylogenetic analysis based on core genome single nucleotide polymorphisms (cg-SNPs), multilocus sequence typing (MLST) and core genome MLST (cg-MLST). Risk factors and clinical outcomes of infections were analyzed through a retrospective case-control study. Potential mechanisms of colistin heteroresistance were evaluated using polymerase chain reaction (PCR), efflux pump inhibition assays and reverse transcription quantitative PCR (RT-qPCR).ResultsA high proportion (24.4%) of the non-resistant strains were colistin-heteroresistant isolates. Among the several ECC species, Enterobacter kobei had the largest percentage (29.4%) of colistin-heteroresistant isolates, followed by Enterobacter hormaechei (20.5%) and Enterobacter bugandensis (20.0%). Notably, only one strain (0.8%; 1/132) of Enterobacter hormaechei was fully resistant to colistin. Different ECC species showed varying heteroresistance levels: Enterobacter roggenkampii, Enterobacter kobei, Enterobacter asburiae and Enterobacter bugandensis displayed high heteroresistance levels (MIC ≥ 128 mg/L). 75% of all ST116 and ST56 strains were heteroresistant to colistin. The infection of ST116 and ST56 strains as well as exposure to cephalosporin antibiotics were independent risk factors for colistin-heteroresistant ECC infections. Mechanistic analysis revealed that heteroresistance strongly correlated with the overexpression of arnA, regulated by the PhoPQ two-component system (TCS). Notably, mgrB had minimal impact. AcrAB-TolC efflux pump genes showed unsynchronized expression; High acrB expression was strongly associated with colistin heteroresistance, while acrA and tolC were not.DiscussionColistin heteroresistance showed species-dependent variations in levels and prevalence rates. The colistin-heteroresistant mechanisms were complex, involving coordinated regulation of multiple genes. These results highlighted the need for tailored antimicrobial stewardship. In addition, the development of direct, reliable and rapid clinical methods for detecting heteroresistance is essential for improving infection management and prevention.https://www.frontiersin.org/articles/10.3389/fcimb.2025.1536058/fullEnterobacter cloacae complexcolistin heteroresistanceresistant subpopulationsprevalencerisk factorsmechanisms |
| spellingShingle | Chunli Wei Jiming Wu Jisheng Zhang Youtao Liang Kaixin Yu Kaixin Yu Mingjing Liao Xushan Liang Jianmin Wang Wenzhang Long Jin Wang Shijian Chen Yang Yang Xue Gong Jie Li Xiaoli Zhang Clinical characteristics, molecular epidemiology and mechanisms of colistin heteroresistance in Enterobacter cloacae complex Frontiers in Cellular and Infection Microbiology Enterobacter cloacae complex colistin heteroresistance resistant subpopulations prevalence risk factors mechanisms |
| title | Clinical characteristics, molecular epidemiology and mechanisms of colistin heteroresistance in Enterobacter cloacae complex |
| title_full | Clinical characteristics, molecular epidemiology and mechanisms of colistin heteroresistance in Enterobacter cloacae complex |
| title_fullStr | Clinical characteristics, molecular epidemiology and mechanisms of colistin heteroresistance in Enterobacter cloacae complex |
| title_full_unstemmed | Clinical characteristics, molecular epidemiology and mechanisms of colistin heteroresistance in Enterobacter cloacae complex |
| title_short | Clinical characteristics, molecular epidemiology and mechanisms of colistin heteroresistance in Enterobacter cloacae complex |
| title_sort | clinical characteristics molecular epidemiology and mechanisms of colistin heteroresistance in enterobacter cloacae complex |
| topic | Enterobacter cloacae complex colistin heteroresistance resistant subpopulations prevalence risk factors mechanisms |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2025.1536058/full |
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