Urinary tract infection caused by a small colony variant form of capnophilic Escherichia coli leading to misidentification and non-reactions in antimicrobial susceptibility tests

Park, Yu Jin; Nguyen, Le Phuong Anh; Pinto, Naina Adren; Kwon, Mi; D’Souza, Roshan; Byun, Jung Hyun; Sung, Heungsup; Yong, Dongeun

doi:10.1186/s13756-018-0438-6

Cited by 15 publications

(14 citation statements)

References 8 publications

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“…Therefore, change in oxygen tension itself in the infected host environment may not be the major selective pressure for SCV development. Our finding of mutations in oxidative respiration related genes was consistent with the overwhelming reports of bacterial SCV deficiencies in heme, menaquinone, and lipoic acid synthesis 4 , 21 , 31 , 32 . Thus, an overarching impression of the SCV degenerative mutations is their association with the essential elements of aerobic living which demands more iron 33 .…”

Section: Discussionsupporting

confidence: 90%

Inactivation of genes in oxidative respiration and iron acquisition pathways in pediatric clinical isolates of Small colony variant Enterobacteriaceae

Greninger

Addetia

Tao

et al. 2021

Sci Rep

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Isolation of bacterial small colony variants (SCVs) from clinical specimens is not uncommon and can fundamentally change the outcome of the associated infections. Bacterial SCVs often emerge with their normal colony phenotype (NCV) co-isolates in the same sample. The basis of SCV emergence in vivo is not well understood in Gram-negative bacteria. In this study, we interrogated the causal genetic lesions of SCV growth in three pairs of NCV and SCV co-isolates of Escherichia coli, Citrobacter freundii, and Enterobacter hormaechei. We confirmed SCV emergence was attributed to limited genomic mutations: 4 single nucleotide variants in the E. coli SCV, 5 in C. freundii, and 8 in E. hormaechei. In addition, a 10.2 kb chromosomal segment containing 11 genes was deleted in the E. hormaechei SCV isolate. Each SCV had at least one coding change in a gene associated with bacterial oxidative respiration and another involved in iron capture. Chemical and genetic rescue confirmed defects in heme biosynthesis for E. coli and C. freundii and lipoic acid biosynthesis in E. hormaachei were responsible for the SCV phenotype. Prototrophic growth in all 3 SCV Enterobacteriaceae species was unaffected under anaerobic culture conditions in vitro, illustrating how SCVs may persist in vivo.

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Section: Discussionsupporting

confidence: 90%

Inactivation of genes in oxidative respiration and iron acquisition pathways in pediatric clinical isolates of Small colony variant Enterobacteriaceae

Greninger

Addetia

Tao

et al. 2021

Sci Rep

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“…Therefore, change in oxygen tension itself in the infected host environment may not be the major selective pressure for SCV development. Our finding of mutations in oxidative respiration related genes was consistent with the overwhelming reports of bacterial SCV deficiencies in heme, menaquinone, and lipoic acid synthesis (4, 21, 29, 30). Thus, an overarching impression of the SCV degenerative mutations is their association with the essential elements of aerobic living which demands more iron (Figure 6) (31).…”

Section: Discussionsupporting

confidence: 90%

“…Clinical isolates such as SCVs that lack these growth characteristics may be easily missed due to their small colony size and failure to grow on standard susceptibility testing media. The role of these alternatively pathways of survival in clinical infections may be significantly underestimated (30). Future work must address the totality of bacterial survival mechanisms, including mechanisms of bacteria persistence via resistance to host iron immunity and oxidative stress by means of anaerobiosis and iron bypass.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of genes in oxidative respiration and iron acquisition pathways in pediatric clinical isolates of small-colony variantEnterobactericeae

Greninger

Addetia

Tao

et al. 2019

Preprint

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25Isolation of bacterial small colony variants (SCVs) from clinical specimens is not uncommon and 26 can fundamentally change the outcome of the associated infections. Bacterial SCVs often 27 emerge with their normal colony phenotype (NCV) co-isolates in the same sample. The genetic 28 and biochemical basis of SCV emergence in vivo is not well understood in Gram-negative 29 bacteria. In this study, we interrogated the causal genetic lesions of SCV growth in three pairs of 30 NCV and SCV co-isolates of Escherichia coli, Citrobacter freundii, and Enterobacter 31 hormaechei. We confirmed the isogenic basis of SCV emergence, as there were only 4 single 32 nucleotide variants in SCV for E. coli, 5 in C. freundii, and 8 in E. hormaechei, with respect to 33 their NCV co-isolate. In addition, a 10.2kb chromosomal segment containing 11 genes was 34 deleted in the E. hormaechei SCV isolate. Intriguingly, each SCV had at least one coding 35 change in a gene associated with bacterial oxidative respiration and another involved iron 36 capture. Chemical rescue confirmed the causal role of heme biosynthesis in E. coli and C. 37 freundii and lipoic acid in E. hormaechei SCV isolates. Genetic rescue restored normal growth 38 under aerobic conditions for fes and hemL in C. freundii; hemL in E. coli; and lipA in E. 39 hormaechei SCV isolates. Prototrophic growth in all 3 SCV Enterobacteriaceae species was 40 unaffected under anaerobic culture conditions in vitro, illustrating how SCVs may persist in vivo 41 by abandoning the highly energetic lifestyle in an iron-limiting environment. We propose that the 42 selective loss of functions in oxidative respiration and iron acquisition is indicative of bacterial 43 virulence attenuation for niche specialization and persistence in vivo. 44 45 Importance 46 Small colony variant (SCV) bacteria are routinely isolated in the clinical microbiology laboratory 47 and can be notoriously difficult to treat. Most studies of the genetic underpinnings of SCV 48 clinical isolates have examined Staphylococcus aureus and few have looked at how SCV 49 emerge in Gram-negative bacteria. Here, we undertook detailed characterization of three 50 clinical isolates of SCV in Escherichia coli, Citrobacter freundii, and Enterobacter hormaechei 51 along with their NCV co-isolates. Genomic sequencing revealed that each SCV had at least 52 one coding change in genes involved in both bacterial oxidative respiration and iron capture. 53Chemical and genetic rescue revealed that both pathways could be responsible for the small 54 colony variant. Each of the SCV showed no growth defect compared to NCV when incubated 55 under anaerobic conditions, indicating a potential mechanism for SCV survival in vivo. We 56 hypothesize that by retreating to anaerobic environments and avoiding escalating iron 57 competition with the host, SCV have adapted to live to see another day. 58 59 65 SCVs were first described in Salmonella typhi over a hundred years ago, prior to the antibiotic 66 era (4). Isolation of SCVs is especially common...

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“…SCVs of E. coli have been isolated from urinary tract infections [10], bacteraemia [11] and chronic hip infections [8] and are therefore increasingly considered clinically relevant [12].…”

Section: Introductionmentioning

confidence: 99%

“…Investigations of SCVs of E. coli are relatively rare but have also been associated with mutations within genes encoding proteins involved in the electron transport chain, including yigP [4], hemB [8] and lipA [9]. SCVs of E. coli have been isolated from urinary tract infections [10], bacteraemia [11] and chronic hip infections [8] and are therefore increasingly considered clinically relevant [12].…”

Section: Introductionmentioning

confidence: 99%

A novel hemA mutation is responsible for a small-colony-variant phenotype in Escherichia coli

2021

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We identified a small colony variant (SCV) of an amoxicillin/clavulanic acid-resistant derivative of a clinical isolate of Escherichia coli from Malawi, which was selected for in vitro in a subinhibitory concentration of gentamicin. The SCV was auxotrophic for hemin and had impaired biofilm formation compared to the ancestral isolates. A single novel nucleotide polymorphism (SNP) in hemA, which encodes a glutamyl-tRNA reductase that catalyses the initial step of porphyrin biosynthesis leading to the production of haem, was responsible for the SCV phenotype. We showed the SNP in hemA resulted in a significant fitness cost to the isolate, which persisted even in the presence of hemin. However, the phenotype quickly reverted during sequential sub-culturing in liquid growth media. As hemA is not found in mammalian cells, and disruption of the gene results in a significant fitness cost, it represents a potential target for novel drug development specifically for the treatment of catheter-associated urinary tract infections caused by E. coli .

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Urinary tract infection caused by a small colony variant form of capnophilic Escherichia coli leading to misidentification and non-reactions in antimicrobial susceptibility tests

Cited by 15 publications

References 8 publications

Inactivation of genes in oxidative respiration and iron acquisition pathways in pediatric clinical isolates of Small colony variant Enterobacteriaceae

Inactivation of genes in oxidative respiration and iron acquisition pathways in pediatric clinical isolates of Small colony variant Enterobacteriaceae

Inactivation of genes in oxidative respiration and iron acquisition pathways in pediatric clinical isolates of small-colony variantEnterobactericeae

A novel hemA mutation is responsible for a small-colony-variant phenotype in Escherichia coli

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