An animal model of limitation of gut colonization by carbapenemase-producing Klebsiella pneumoniae using rifaximin

Xenofontos, Eleni; Renieris, Georgios; Kalogridi, Maria; Droggiti, Dionyssia-Eirini; Synodinou, Kalliopi D.; Damoraki, Georgia; Koufargyris, Panagiotis; Sabracos, Labros; Giamarellos‐Bourboulis, Evangelos J.

doi:10.1038/s41598-022-07827-8

Cited by 5 publications

(5 citation statements)

References 37 publications

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“…positively related to the concentration of bilirubin (27). However, such antibiotics should significantly inhibit Klebsiella, which is inconsistent with the results of this study and is worth for further exploration (28). Functional prediction results can also be used as a reference for future research.…”

Section: Discussioncontrasting

confidence: 61%

Characteristics of intestinal microbiota in infants with late-onset breast milk jaundice

Guo,

Liu,

Cui

et al. 2023

Front. Nutr.

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IntroductionIn this paper, microbiota analysis was determined to analyze the structure and difference of intestinal microbiota between LBMJ (late-onset breast milk jaundice) infants and healthy individuals.MethodsWe collected fresh fecal samples from 13 infants with LBMJ and 13 healthy individuals, then determined the intestinal microbiota by 16 s rRNA sequencing. The differences of microbiota structure, diversity and functional characteristics between the two groups were analyzed, and the correlation between dominant genus and TcB (transcutaneous bilirubin) value was calculated.ResultsIn this study, there were no significant differences in maternal demographic characteristics, neonatal status and macronutrients in breast milk between the two groups (p > 0.05). There are differences in the structure of intestinal microbiota between LBMJ and the control group. At the genus level, the relative abundance of Klebsiella in the case group is high (p < 0.05). At the same time, correlation analysis indicates that the abundance of Klebsiella is positively correlated with TcB value. The intestinal microbiota richness and diversity (Alpha diversity and Beta diversity) of the two groups were significantly different (p < 0.05). LEfSe analysis showed that 25 genera including Klebsiella was significantly enriched in the LBMJ infants, and the other 17 species are enriched in the control group. Functional prediction analysis indicated that 42 metabolic pathways may be related to the occurrence of LBMJ.ConclusionIn conclusion, characteristic changes are seen in intestinal microbiota compositions between LBMJ infants and the healthy controls. Klebsiella is closely associated with the severity of the disease, which may be due to enhanced β-glucuronidase activity.

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Section: Discussioncontrasting

confidence: 61%

Characteristics of intestinal microbiota in infants with late-onset breast milk jaundice

Guo,

Liu,

Cui

et al. 2023

Front. Nutr.

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“…3). These ndings suggest that Rifaximin is a promising antibacterial agent against KP, warranting further investigation of its therapeutic potential, particularly in the face of multidrug-resistant strains [42].…”

Section: Determination Of Mic and Mbc For Rifaximin Against Kpmentioning

confidence: 94%

Repurposing Rifaximin against Klebsiella pneumoniae via Targeting of Transcription Anti-termination Protein RfaH for Novel Antimicrobial Development

Ashraf,

Choudhary,

Khan

et al. 2024

Preprint

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Anti-termination protein RfaH plays a crucial role in promoting virulence across various Gram-negative pathogens, including Klebsiella pneumoniae (KP). RfaH directly interacts with RNA-polymerase and ribosomes, which in turn facilitates the activation of operons associated with capsule, cell wall, and pilus biosynthesis. This study aimed to investigate the repurposing potential of rifaximin, a well-established antibiotic, against KP by strategically targeting RfaH, a pivotal anti-terminator protein in transcription. Fluorescence studies observed an excellent binding affinity between rifaximin and RfaH (Ka = 7.38 x 106M−1). Intriguingly, rifaximin treatment causes a significant reduction in capsule production in KP when compared to untreated controls, elucidating its inhibitory influence on RfaH activity. The minimum inhibitory concentration for Rifaximin was calculated as 100µM and a minimum bactericidal concentration of 200µM against KP (ATCC 700603 strain). Docking and MD simulation studies provided detailed atomic insights into the Rifaximin binding to RfaH and structural dynamics of the RfaH-Rifaximin complex. These multifaceted findings collectively investigated the potential of rifaximin as a repurposed antibiotic against KP. Finally, a strong interaction of RfaH with rifaximin and subsequent inhibition of the growth of KP provides a novel avenue for antimicrobial development for addressing the persistent global challenge of antibiotic-resistant infections.

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“…The gut colonization of mice has been widely studied in recent years, yet the results have been mixed. While some studies have used low-complexity-microbiota mice (Göttig et al, 2015) or antibiotics treatment such as ampicillin to establish colonization (Xenofontos et al, 2022), direct feeding to achieve colonization has proven to be challenging due to the complexity of the mice microbiome and immune system. As such, the high usage of mice in number of experiments without certainty of successful colonization is an issue of ethical concern.…”

Section: Decolonization Of Larvae Gutmentioning

confidence: 99%

Bacteriophage-mediated decolonization ofEnterobacteriaceaein a novelGalleria mellonellagut colonization model

Mirza

Jacob

Nietzsche

et al. 2023

Preprint

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Galleria mellonella larvae have emerged as an invertebrate model for studying bacterial pathogenesis and novel therapeutic options due to ethical concerns associated with the use of mammalian models such as mice. The benefits of using G. mellonella larvae include a less complex microbiome in the gut, making it suitable for gut colonization studies. The intestinal colonization of Klebsiella pneumoniae (Kp) and Escherichia coli (Ec), two of the most antibiotic-resistant bacteria on the World Health Organization's (WHO) priority list, plays a key role in the spread of antibiotic resistance. Bacteriophage therapy is emerging as a promising alternative for antibiotic-resistant bacteria due to its ability to specifically target and infect bacterial hosts, making it suitable for gut decontamination. This study aimed to establish a novel Enterobacteriaceae G. mellonella larvae gut colonization model and compare the efficacy of conventional antibiotic treatment with a one-time phage cocktail in decolonizing the gut. Larvae were force-fed with different concentrations of bacterial doses of K. pneumoniae and E. coli at 0 h, 24 h, and 48 h, followed by survival monitoring at 24 h intervals. After 48 h and 120 h of the last force feed, the colony forming unit (CFU) count in the gut was evaluated. After successful colonization, larvae were one-time force-fed with either a 107 PFU/larvae bacteriophage cocktail or with ciprofloxacin 4 mg/L or meropenem 2 mg/L. After 24 h post phage feeding, CFU counts were determined. Three bacterial doses of 106 CFU/larvae led to a stable gut colonization in the larvae gut regardless of the K. pneumoniae and E. coli strains. Bacteriophage force-feeding reduced bacterial colonization by 4 log10 CFU/larvae whereas antibiotic treatment led to a 2 log10 CFU/larvae reduction compared to the control. The novel alternative G. mellonella model for gut colonization studies can be used for proof-of-concept studies, reducing or even obviating the number of follow-up experiments in vertebrate models.

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An animal model of limitation of gut colonization by carbapenemase-producing Klebsiella pneumoniae using rifaximin

Cited by 5 publications

References 37 publications

Characteristics of intestinal microbiota in infants with late-onset breast milk jaundice

Characteristics of intestinal microbiota in infants with late-onset breast milk jaundice

Repurposing Rifaximin against Klebsiella pneumoniae via Targeting of Transcription Anti-termination Protein RfaH for Novel Antimicrobial Development

Bacteriophage-mediated decolonization ofEnterobacteriaceaein a novelGalleria mellonellagut colonization model

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