Showing papers by "Scott J. Hultgren published in 2022"
TL;DR: In this paper , the role of the microbiota in recurrent urinary tract infections (rUTIs) remains unclear, and the authors conducted a year-long study of women with and without a history of rUTI, from whom they collected urine, blood and monthly faecal samples for metagenomic and transcriptomic interrogation.
Abstract: Recurrent urinary tract infections (rUTIs) are a major health burden worldwide, with history of infection being a significant risk factor. While the gut is a known reservoir for uropathogenic bacteria, the role of the microbiota in rUTI remains unclear. We conducted a year-long study of women with (n = 15) and without (n = 16) history of rUTI, from whom we collected urine, blood and monthly faecal samples for metagenomic and transcriptomic interrogation. During the study 24 UTIs were reported, with additional samples collected during and after infection. The gut microbiome of individuals with a history of rUTI was significantly depleted in microbial richness and butyrate-producing bacteria compared with controls, reminiscent of other inflammatory conditions. However, Escherichia coli gut and bladder populations were comparable between cohorts in both relative abundance and phylogroup. Transcriptional analysis of peripheral blood mononuclear cells revealed expression profiles indicative of differential systemic immunity between cohorts. Altogether, these results suggest that rUTI susceptibility is in part mediated through the gut-bladder axis, comprising gut dysbiosis and differential immune response to bacterial bladder colonization, manifesting in symptoms.
36 citations
TL;DR: The Strain Genome Explorer (StrainGE) toolkit as mentioned in this paper deconvolves strain mixtures and characterizes component strains at the nucleotide level from short-read metagenomic sequencing with higher sensitivity and resolution than other tools.
Abstract: Abstract Human-associated microbial communities comprise not only complex mixtures of bacterial species, but also mixtures of conspecific strains, the implications of which are mostly unknown since strain level dynamics are underexplored due to the difficulties of studying them. We introduce the Strain Genome Explorer (StrainGE) toolkit, which deconvolves strain mixtures and characterizes component strains at the nucleotide level from short-read metagenomic sequencing with higher sensitivity and resolution than other tools. StrainGE is able to identify strains at 0.1x coverage and detect variants for multiple conspecific strains within a sample from coverages as low as 0.5x.
23 citations
TL;DR: There is an urgent need to better understand uropathogen dynamics within host-associated reservoirs to develop treatment options that limit morbidity and mortality due to currently treatable common infections.
Abstract: Introduction The widespread use of antibiotics, in both healthcare and agriculture, has led to the emergence of antibioticresistant bacteria, decreasing our ability to effectively treat common infections. With predictions of antibiotic resistance reaching a tipping point, it is imperative that we develop novel, antibiotic-sparing medicines to avoid a future of increasing mortality due to currently treatable common infections. In the United States, 15% of antibiotics are prescribed for the treatment of urinary tract infections (UTIs) (1) affecting millions of women annually. For those suffering acute UTI, 25% experience recurrent UTIs (rUTIs) (1), involving several infections per year, that require multiple antibiotic courses. Recent history of a UTI is a known risk factor for rUTI (2), yet the mechanisms leading to recurrence are mostly unknown. In addition, antibiotic resistance is making UTIs harder to treat and often necessitates using broad-spectrum antibiotics. Ironically, antibiotic use is also a significant risk factor for a UTI (3), possibly due to associated deleterious effects on the gut microbiota, among which most uropathogens reside. That approximately 50% of rUTIs are caused by the same strain that caused the initial infection (4) argues for a host-associated reservoir that is not adequately cleared by current treatments. Thus, there is an urgent need to better understand uropathogen dynamics within host-associated reservoirs to develop treatment options that limit morbidity and [...] Viewpoint
8 citations
TL;DR: A new class of antibiotics based on a ring-fused 2-pyridone backbone is described, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria.
Abstract: Significance The increasing prevalence of antibiotic resistant bacterial infections represents a significant public health crisis, necessitating the development of new therapeutics that work alone or in combination to increase efficacy of standard-of-care antibiotics. We describe a new class of antibiotics, that we have termed GmPcides, that have antibacterial activity against Gram-positive bacteria including multidrug-resistant pathogens. GmPcides effectively stop the growth of dividing and kill stationary phase nondividing enterococcal cells. Additionally, sublethal doses of GmPcides have additive to synergistic effects when combined with several different classes of standard-of-care antibiotics to treat multidrug-resistant bacteria. Thus, GmPcides hold potential to be used alone and in combination with existing antibiotics to combat antibiotic resistant infections caused by Gram-positive bacteria.
2 citations
TL;DR: The complete genome sequence of MRSA-1369, which consists of one chromosome (2.87 Mb) and two plasmids (16.68 kb and 3.13 kb) will serve as a reference genome for future Staphylococcus aureus pathogenesis and multiomic studies.
Abstract: MRSA-1369 is a uropathogenic methicillin-resistant Staphylococcus aureus (MRSA) strain. Here, we present the complete genome sequence of MRSA-1369, which consists of one chromosome (2.87 Mb) and two plasmids (16.68 kb and 3.13 kb). This will serve as a reference genome for future Staphylococcus aureus pathogenesis and multiomic studies. ABSTRACT MRSA-1369 is a uropathogenic methicillin-resistant Staphylococcus aureus (MRSA) strain. Here, we present the complete genome sequence of MRSA-1369, which consists of one chromosome (2.87 Mb) and two plasmids (16.68 kb and 3.13 kb). This will serve as a reference genome for future Staphylococcus aureus pathogenesis and multiomic studies.
1 citations
TL;DR: The trajectory of P. aeruginosa in breast implant–associated infections was strain-dependent, and strains could exhibit acute symptomatic or chronic asymptomatic colonization.
Abstract: Background: Pseudomonas aeruginosa accounts for 7 to 22 percent of breast implant–associated infections, which can result in reconstructive failures and explantation. Investigating host-pathogen-device interactions in mice and patient samples will improve the understanding of colonization mechanisms, for targeted treatments and clinical guidelines. Methods: Mice with and without implants were infected with PAO1 laboratory strain or BIP2 or BIP16 clinical strains and killed at 1 day or 7 days after infection to evaluate for colonization of implants and underlying tissues by means of colony-forming unit enumeration. Immunostaining was performed on mouse implants, human tissue expanders colonized by BIP2, and acellular dermal matrix colonized by BIP16. Results: Colonization of tissues and smooth implants by P. aeruginosa was strain-dependent: at 1 day after infection, all strains acutely infected tissues with and without implants with colonization levels reflecting growth rates of individual strains. At 7 days after infection, PAO1 caused colonization of approximately 105 colony-forming units/100 mg of tissue but required implant presence, whereas in mice infected with BIP2/BIP16, colony-forming units were below the limit of detection with or without implants. Immunofluorescence staining of mouse implants, however, demonstrated continued presence of BIP2 and BIP16. Staining showed co-localization of all strains with fibrinogen, collagen I, and collagen III on mouse and human samples. Conclusions: The trajectory of P. aeruginosa in breast implant–associated infections was strain-dependent, and strains could exhibit acute symptomatic or chronic asymptomatic colonization. With strains causing clinical symptoms, the presence of an implant significantly worsened infection. For asymptomatic colonizers, further studies investigating their long-term impacts, especially during periods of immunosuppression in hosts, are needed.
1 citations
TL;DR: In this article , the significance of specific metabolic pathways during MRSA uropathogenesis was determined in the mouse model of catheter-associated UTI (CAUTI), which may be attributed to its increased membrane hydrophobicity and higher susceptibility to killing by human blood.
Abstract: While Staphylococcus aureus has historically not been considered a uropathogen, S. aureus urinary tract infection (UTI) is clinically significant in certain patient populations, including those with chronic indwelling urinary catheters. Moreover, most S. aureus strains causing catheter-associated UTI (CAUTI) are methicillin-resistant S. aureus (MRSA). ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of complicated urinary tract infection (UTI) associated with the use of indwelling urinary catheters. Previous reports have revealed host and pathogen effectors critical for MRSA uropathogenesis. Here, we sought to determine the significance of specific metabolic pathways during MRSA UTI. First, we identified four mutants from the Nebraska transposon mutant library in the MRSA JE2 background that grew normally in rich medium but displayed significantly reduced growth in pooled human urine (HU). This prompted us to transduce the uropathogenic MRSA 1369 strain with the transposon mutants in sucD and fumC (tricarboxylic acid [TCA] cycle), mtlD (mannitol metabolism), and lpdA (pyruvate oxidation). Notably, sucD, fumC, and mtlD were also significantly upregulated in the MRSA 1369 strain upon exposure to HU. Compared to the WT, the MRSA 1369 lpdA mutant was significantly defective for (i) growth in HU, and (ii) colonization of the urinary tract and dissemination to the kidneys and the spleen in the mouse model of catheter-associated UTI (CAUTI), which may be attributed to its increased membrane hydrophobicity and higher susceptibility to killing by human blood. In contrast to their counterparts in the JE2 background, the sucD, fumC, and mtlD mutants in the MRSA 1369 background grew normally in HU; however, they displayed significant fitness defects in the CAUTI mouse model. Overall, identification of novel metabolic pathways important for the urinary fitness and survival of MRSA can be used for the development of novel therapeutics. IMPORTANCE While Staphylococcus aureus has historically not been considered a uropathogen, S. aureus urinary tract infection (UTI) is clinically significant in certain patient populations, including those with chronic indwelling urinary catheters. Moreover, most S. aureus strains causing catheter-associated UTI (CAUTI) are methicillin-resistant S. aureus (MRSA). MRSA is difficult to treat due to limited treatment options and the potential to deteriorate into life-threatening bacteremia, urosepsis, and shock. In this study, we found that pathways involved in pyruvate oxidation, TCA cycle, and mannitol metabolism are important for MRSA fitness and survival in the urinary tract. Improved understanding of the metabolic needs of MRSA in the urinary tract may help us develop novel inhibitors of MRSA metabolism that can be used to treat MRSA-CAUTI more effectively.