MgrB-Dependent Colistin Resistance in Klebsiella pneumoniae Is Associated with an Increase in Host-to-Host Transmission

Bray, Andrew S.; Smith, Richard D.; Hudson, Andrew W; Hernandéz, Giovanna; Young, Taylor M; George, Hannah E.; Ernst, Robert K.; Zafar, M. Ammar

doi:10.1128/mbio.03595-21

Cited by 24 publications

(21 citation statements)

References 67 publications

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“…However, a high variety of other non-described mutations were detected, supporting the urgent need for reliable genotypic-phenotypic correlations to explain colistin resistance mechanisms (51). Such a variety and frequency of chromosomal mutations in ColR-Kp detected in different studies and environments (26, 43, 50, 51) suggest they could play a role in adaptive features other than colistin resistance (e.g., mgrB inactivation in environmental K. pneumoniae survival and transmission; phoPQ or pmrB mutations in chlorhexidine tolerance) (52)(53)(54). Also, some of these mutations do not confer significant biological cost (55,56) which may explain the occurrence of colistin-resistant mcrnegative K. pneumoniae long after colistin withdrawal.…”

Section: Discussionmentioning

confidence: 91%

From farm to fork: persistence of clinically-relevant multidrug-resistant and copper-tolerantKlebsiella pneumoniaelong after colistin withdrawal in poultry production

Mourão

Ribeiro-Almeida

Novais

et al. 2023

Preprint

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The concern of colistin-resistant bacteria in animal-food-environmental-human ecosystems prompted the poultry sector to implement colistin restrictions and explore alternative trace metals/copper feed supplementation. The impact of these strategies on the selection and persistence of colistin-resistant Klebsiella pneumoniae (Kp) in the whole poultry-production chain needs clarification. We assessed colistin-resistant and copper-tolerant Kp occurrence in chicken raised with inorganic and organic copper-formulas from one-day-old chicks to meat (7 farms/2019-2020), after long-term colistin withdrawal (>2-years). Clonal diversity and Kp adaptive features were characterized by cultural, molecular, and whole-genome-sequencing (WGS) approaches. Most chicken-flocks (75%) carried Kp at early+pre-slaughter stages, with a significant decrease (p<0.05) in meat batches (17%) and sporadic water/feed contamination. High rates (>50%) of colistin-resistant/mcr-negative Kp were observed among faecal samples, independently of feed. Most samples carried multidrug-resistant (90%) and copper-tolerant isolates (81%; pco+sil/MICCuSO4 ≥16mM). WGS revealed accumulation of colistin resistance associated mutations and F-type multireplicon plasmids carrying antibiotic resistance and metal/copper-tolerance genes. The Kp population was polyclonal, with various lineages dispersed throughout poultry production. ST15-KL19, ST15-KL146 and ST392-KL27, and IncF plasmids were similar to those from global human clinical isolates, suggesting chicken-production as a reservoir/source of clinically-relevant Kp lineages and genes with potential risk to humans through food and/or environmental exposure. Despite long-term colistin ban limited mcr spread, it was ineffective in controlling colistin-resistant/mcr-negative Kp, regardless of feed. This study provides crucial insights into the persistence of clinically-relevant Kp in the poultry-production chain and highlights the need for continued surveillance and proactive food safety actions within a One-Health perspective.

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Section: Discussionmentioning

confidence: 91%

From farm to fork: persistence of clinically-relevant multidrug-resistant and copper-tolerantKlebsiella pneumoniaelong after colistin withdrawal in poultry production

Mourão

Ribeiro-Almeida

Novais

et al. 2023

Preprint

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“…For the PhoQP/MgrB system from K. pneumoniae this idea has been recently proposed. Bray et al (2021) [73] demonstrated that loss of MgrB in colistin resistant- K. pneumoniae is accompanied by compromised gastrointestinal colonisation efficacy. Like our results, this study too reported the overproduction of RpoS in mgrB -deficient K. pneumoniae .…”

Section: Discussionmentioning

confidence: 99%

“…Like our results, this study too reported the overproduction of RpoS in mgrB -deficient K. pneumoniae . However, the authors reported that RpoS overproduction was beneficial in a model for pathogen transmission [73]. Thus, life-history and growth context are both likely to have a strong influence on how deregulation of gene expression translates to organismal fitness.…”

Section: Discussionmentioning

confidence: 99%

Adaptive and maladaptive consequences of deregulation in a bacterial gene regulatory network

Vinchhi

Yelpure

Balachandran

et al. 2023

Preprint

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The archetypal PhoQP two-component system from Enterobacteria regulates crucial pathways like magnesium homeostasis in Escherichia coli and virulence factor expression in Salmonella enterica. Previously we had reported that a laboratory strain of E. coli rapidly accumulated loss-of-function mutations in the mgrB gene, a negative feedback regulator of PhoQP, when evolved in the presence of the antibiotic trimethoprim (Patel and Matange, eLife 2021). Hyperactive PhoQP enhanced the expression of dihydrofolate reductase, target of trimethoprim, resulting in antibiotic tolerance. Here we ask, firstly, how important are mutations in mgrB for the evolution of trimethoprim resistance? We report that MgrB loss, though itself only mildly beneficial, facilitates the evolution of resistance by enhancing the fixation probability of trimethoprim-resistant bacteria under selection. Secondly, we investigate why negative feedback may be needed in the PhoQP system. We show that under drug-free conditions MgrB is required to mitigate the fitness costs of pervasive gene dysregulation by hyperactive PhoQP. Using RNA-seq transcriptomics and genetic analyses, we demonstrate that PhoQP-hyperactivation perturbs the balance of RpoS and RpoD regulated transcriptional programs, and spontaneous mutations in rpoS rectify this imbalance. We propose that relative adaptive and maladaptive consequences of deregulation explain the evolution of negative feedback in bacterial gene regulatory networks.

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“…When a bacterium becomes resistant to colistin, it can also simultaneously become impervious to components of the host"s defense system, such as lysozymes and cationic antimicrobial peptides (CAMPs), principally as they act on the same target of polymyxins, hence the main mechanism of resistance of K. pneumoniae is genetic regulation of LPS formation, particularly lipid A (31) .…”

Section: Polymyxin Resistancementioning

confidence: 99%

An Updated Outline of Klebsiella pneumoniae Resistance: Mechanisms and Treatments

Soliman

Agban

2022

Egyptian Journal of Medical Microbiology

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Klebsiella pneumoniae (K. pneumoniae) is the most prominent type of Klebsiella spp. K. pneumoniae has become a worldwide health threat nowadays due to the emergence of hypervirulence and the extended-spectrum β-lactamases (ESBLs) producing strains that lead to the etiologies of hospital-acquired infections (HAI) and community-acquired infections (CAI). To survive within the host, the bacterium acquires virulence traits and techniques to resist antibiotics and the immune system response, hence it gradually becomes multidrug-resistant (MDR). Consequently, more antibiotics are rendered ineffective and thus inappropriate, causing more deteriorating clinical conditions, leading to a high mortality rate. While the vaccine of K. pneumoniae is still in progress, and since we are long past the beginning of antibiotic use, new concepts came to play to fight the bacterial infection such as the use of bacteriophage to destroy the prokaryotic cell and enhancement of the immune system. This article covers the most common genetic and structural mechanisms of resistance by which K. pneumoniae exhibits its resilience against the defense system and various antibiotics. It also reviews the epidemiology, the leading sites of infections, and possible treatment options for future use.

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MgrB-Dependent Colistin Resistance in Klebsiella pneumoniae Is Associated with an Increase in Host-to-Host Transmission

Cited by 24 publications

References 67 publications

From farm to fork: persistence of clinically-relevant multidrug-resistant and copper-tolerantKlebsiella pneumoniaelong after colistin withdrawal in poultry production

From farm to fork: persistence of clinically-relevant multidrug-resistant and copper-tolerantKlebsiella pneumoniaelong after colistin withdrawal in poultry production

Adaptive and maladaptive consequences of deregulation in a bacterial gene regulatory network

An Updated Outline of Klebsiella pneumoniae Resistance: Mechanisms and Treatments

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