Bovine Streptococcus uberis Intramammary Infections and Mastitis

Krömker, Volker

doi:10.4172/2327-5073.1000157

Cited by 38 publications

(42 citation statements)

References 86 publications

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“…Bovine mastitis, an inflammatory disease of the bovine mammary gland, is the leading cause for antimicrobial use in the dairy industry worldwide (5,6). The Grampositive pathogen Streptococcus uberis is a common environmental cause of bovine mastitis (7). Due to the ubiquity of environmental pathogens such as S. uberis in the dairy environment, prevention of environmental mastitis is particularly challenging and relies heavily on antimicrobial sanitizers (8,9).…”

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confidence: 99%

Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2

Harbison-Price

Ferguson

Heikal

et al. 2020

mSphere

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Globally, more antimicrobials are used in food-producing animals than in humans, and the extensive use of medically important human antimicrobials poses a significant public health threat in the face of rising antimicrobial resistance (AMR). The development of novel ionophores, a class of antimicrobials used exclusively in animals, holds promise as a strategy to replace or reduce essential human antimicrobials in veterinary practice. PBT2 is a zinc ionophore with recently demonstrated antibacterial activity against several Gram-positive pathogens, although the underlying mechanism of action is unknown. Here, we investigated the bactericidal mechanism of PBT2 in the bovine mastitis-causing pathogen, Streptococcus uberis. In this work, we show that PBT2 functions as a Zn2+/H+ ionophore, exchanging extracellular zinc for intracellular protons in an electroneutral process that leads to cellular zinc accumulation. Zinc accumulation occurs concomitantly with manganese depletion and the production of reactive oxygen species (ROS). PBT2 inhibits the activity of the manganese-dependent superoxide dismutase, SodA, thereby impairing oxidative stress protection. We propose that PBT2-mediated intracellular zinc toxicity in S. uberis leads to lethality through multiple bactericidal mechanisms: the production of toxic ROS and the impairment of manganese-dependent antioxidant functions. Collectively, these data show that PBT2 represents a new class of antibacterial ionophores capable of targeting bacterial metal ion homeostasis and cellular redox balance. We propose that this novel and multitarget mechanism of PBT2 makes the development of cross-resistance to medically important antimicrobials unlikely. IMPORTANCE More antimicrobials are used in food-producing animals than in humans, and the extensive use of medically important human antimicrobials poses a significant public health threat in the face of rising antimicrobial resistance. Therefore, the elimination of antimicrobial crossover between human and veterinary medicine is of great interest. Unfortunately, the development of new antimicrobials is an expensive high-risk process fraught with difficulties. The repurposing of chemical agents provides a solution to this problem, and while many have not been originally developed as antimicrobials, they have been proven safe in clinical trials. PBT2, a zinc ionophore, is an experimental therapeutic that met safety criteria but failed efficacy checkpoints against both Alzheimer’s and Huntington’s diseases. It was recently found that PBT2 possessed potent antimicrobial activity, although the mechanism of bacterial cell death is unresolved. In this body of work, we show that PBT2 has multiple mechanisms of antimicrobial action, making the development of PBT2 resistance unlikely.

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confidence: 99%

Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2

Harbison-Price

Ferguson

Heikal

et al. 2020

mSphere

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“…We also detected bacterial species known to cause bovine mastitis: Klebsiella pneumoniae 15 , and Streptococcus uberis 16 at very high confidence. Mastitis in dairy cattle is a potentially fatal disease, causing necrosis of udder tissue, and affects large proportions of cows 17,18 .…”

Section: Resultsmentioning

confidence: 86%

What's in my pot? Real-time species identification on the MinION

Juul¹,

Izquierdo

Hurst

et al. 2015

Preprint

112

101

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Whole genome sequencing on next-generation instruments provides an unbiased way to identify the organisms present in complex metagenomic samples. However, the time-to-result can be protracted because of fixed-time sequencing runs and cumbersome bioinformatics workflows. This limits the utility of the approach in settings where rapid species identification is crucial, such as in the quality control of food-chain components, or in during an outbreak of an infectious disease. Here we present What′s in my Pot? (WIMP), a laboratory and analysis workflow in which, starting with an unprocessed sample, sequence data is generated and bacteria, viruses and fungi present in the sample are classified to subspecies and strain level in a quantitative manner, without prior knowledge of the sample composition, in approximately 3.5 hours. This workflow relies on the combination of Oxford Nanopore Technologies′ MinION ™ sensing device with a real-time species identification bioinformatics application.

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“…An inherent weakness in routine methods seems to be that the expression of characteristics varies by Strep. uberis isolate (Odierno et al, 2006;Krömker et al, 2014;Duarte et al, 2015). The routine identification procedure could be misleading with respect to the distinction between atypical Strep.…”

Section: Discussionmentioning

confidence: 99%

“…uberis and Strep. parauberis using routine identification procedures (Khan et al, 2003;Wyder et al, 2011;Krömker et al, 2014), but both Strep. parauberis isolates failed to show blue-colored colony growth on MRAM.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic accuracy of a standardized scheme for identification of Streptococcus uberis in quarter milk samples: A comparison between conventional bacteriological examination, modified Rambach agar medium culturing, and 16S rRNA gene sequencing

Wald

Baumgartner

Urbantke

et al. 2017

Journal of Dairy Science

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Bacteriological examination of milk samples is a prerequisite for pathogen-specific therapy and aids in limiting antimicrobial resistance. The aims of this study were to establish a standardized scheme for reliable Streptococcus uberis identification in routine diagnosis and to evaluate the accuracy of conventional tests and growing patterns of Strep. uberis on a selective medium (modified Rambach agar medium, MRAM) using 16S rRNA gene sequencing analysis as a reference method. We obtained isolates of presumptive Strep. uberis (n = 336) from quarter milk samples of dairy cows with intramammary infections and classified the isolates into 2 clusters using biochemical characterization. In cluster 1 (n = 280), cocci grew as non-hemolytic colonies, hydrolyzing esculin, carrying no Lancefield antigen (A/B/C/D/G) or Christie Atkins Munch-Petersen factor, and their growth was inhibited on an Enterococcus agar. Production of β-d-galactosidase on MRAM was shown by 257 of the cluster 1 isolates (91.79%), and 16S rRNA gene sequencing verified 271 (96.79%) of the isolates to be Strep. uberis. In 264 isolates (94.29%), MRAM agreed with the sequencing results. In cluster 2 (n = 56), isolates showed different characteristics: 37 (66.07%) were β-d-galactosidase-positive, and based on 16S sequencing results, 36 (64.29%) were identified correctly as Strep. uberis using biochemical methods. Identification success in this group differed significantly between routine diagnosis and MRAM application: MRAM agreed with sequencing results in 47 isolates (83.93%). To identify Strep. uberis and differentiate it from other lactic acid bacteria in routine diagnosis, we suggest using catalase reaction, hemolysis, esculin hydrolysis, and growth on enterococci agar. Isolates that show a typical biochemical profile can be identified satisfactorily with these tests. For Strep. uberis isolates with divergent patterns, application of MRAM as a follow-up test increased the diagnostic accuracy to 94.64%.

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Bovine Streptococcus uberis Intramammary Infections and Mastitis

Cited by 38 publications

References 86 publications

Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2

Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2

What's in my pot? Real-time species identification on the MinION

Diagnostic accuracy of a standardized scheme for identification of Streptococcus uberis in quarter milk samples: A comparison between conventional bacteriological examination, modified Rambach agar medium culturing, and 16S rRNA gene sequencing

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