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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Comparative Molecular and Immunoregulatory Analysis of Extracellular Vesicles from Candida albicans and Candida auris

Candida auris is a recently described multidrug-resistant pathogenic fungus that is increasingly responsible for health care-associated outbreaks across the world. Bloodstream infections of this fungus cause death in up to 70% of cases. Aggravating this scenario, the disease-promoting mechanisms of C. auris are poorly understood. Fungi release extracellular vesicles (EVs) that carry a broad range of molecules, including proteins, lipids, carbohydrates, pigments, and RNA, many of which are virulence factors. Here, we carried out a comparative molecular characterization of C. auris and Candida albicans EVs and evaluated their capacity to modulate effector mechanisms of host immune defense. Using proteomics, lipidomics, and transcriptomics, we found that C. auris released EVs with payloads that were significantly different from those of EVs released by C. albicans. EVs released by C. auris potentiated the adhesion of this yeast to an epithelial cell monolayer, while EVs from C. albicans had no effect. C. albicans EVs primed macrophages for enhanced intracellular yeast killing, whereas C. auris EVs promoted survival of the fungal cells. Moreover, EVs from both C. auris and C. albicans induced the activation of bone marrow-derived dendritic cells. Together, our findings show distinct profiles and properties of EVs released by C. auris and by C. albicans and highlight the potential contribution of C. auris EVs to the pathogenesis of this emerging pathogen.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Molecular analysis and essentiality of Aro1 shikimate biosynthesis multi-enzyme in Candida albicans

In the human fungal pathogen Candida albicans, ARO1 encodes an essential multi-enzyme that catalyses consecutive steps in the shikimate pathway for biosynthesis of chorismate, a precursor to folate and the aromatic amino acids. We obtained the first molecular image of C. albicans Aro1 that reveals the architecture of all five enzymatic domains and their arrangement in the context of the full-length protein. Aro1 forms a flexible dimer allowing relative autonomy of enzymatic function of the individual domains. Our activity and in cellulo data suggest that only four of Aro1’s enzymatic domains are functional and essential for viability of C. albicans, whereas the 3-dehydroquinate dehydratase (DHQase) domain is inactive because of active site substitutions. We further demonstrate that in C. albicans, the type II DHQase Dqd1 can compensate for the inactive DHQase domain of Aro1, suggesting an unrecognized essential role for this enzyme in shikimate biosynthesis. In contrast, in Candida glabrata and Candida parapsilosis, which do not encode a Dqd1 homolog, Aro1 DHQase domains are enzymatically active, highlighting diversity across Candida species.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Detection of Candida DNA in peritoneal fluids by PCR assay optimizing the diagnosis and treatment for intra-abdominal candidiasis in high-risk ICU patients: A prospective cohort study

Background Intra-abdominal candidiasis (IAC) is the predominant type of invasive candidiasis with high mortality in critically ill patients. This study aimed to investigate whether the polymerase chain reaction (PCR) assay for detecting Candida DNA in peritoneal fluids (PF) is useful in diagnosing and management of IAC in high-risk patients in intensive care unit (ICU). Methods A prospective single-center cohort study of surgical patients at high risk for IAC was conducted in the ICU. PF was collected from the abdominal drainage tubes (within 24 h) or by percutaneous puncture. Direct PF smear microscopy, PF culture, blood culture, and serum (1–3)-β-D-glucan were performed in all patients. For Candida PCR assay, the ITS1/ITS4 primers that targeted the ITS1-5.8 s-ITS2 regions were used for PCR, and sequencing analysis was used to identify the pathogen at the species level. IAC was defined according to the 2013 European consensus criteria. Results Among 83 patients at high risk for IAC, the IAC criteria were present in 17 (20.5%). The sensitivity and specificity of the Candida PCR assay were 64.7 and 89.4%, respectively, and the area under the receiver operating characteristic curve was 0.77 (95% CI: 0.63–0.91). In this cohort, the positive predictive value and negative predictive value were 90.8% (95% CI: 80.3–96.2%) and 61.1% (95% CI: 36.1–81.7%), respectively. Diagnostic consistency was moderate (kappa 0.529, p < 0.001) according to the 2013 European consensus criteria. Conclusion Detection of Candida DNA in PF using PCR can be considered an adjunct to existing routine diagnostic tools which may optimize the diagnosis and antifungal treatment of IAC in high-risk patients in the ICU.

Xie, Min↗
DOE OSTI2023

Characterization of Oral Candida spp. Biofilms in Children and Adults Carriers from Eastern Europe and South America

Background: Candida albicans and non-Candida albicans Candida species (NCACs) are known to colonize and invade various tissues, including the oral mucosa. In this work, we aimed to characterize mature biofilms of several Candida spp. clinical isolates (n = 33) obtained from the oral mucosa of children, adults, and elders of Eastern Europe and South America. Methods: Each strain was evaluated for its capacity to form biofilms in terms of total biomass using the crystal violet assay and for matrix components production (proteins and carbohydrates) using the BCA and phenol-sulfuric tests, respectively. The effect of different antifungals on biofilm formation was studied. Results: in the children’s group, a predominance of C. krusei (81%) was observed, while, among adults, the main species was C. albicans (59%). Most strains showed a reduced response to antimicrobial drugs when in biofilm form (p < 0.01). Moreover, it was observed that strains isolated from children produced more matrix, with higher levels of protein and polysaccharides. Conclusions: children were more likely to be infected by NCACs than adults. More importantly, these NCACs were able to form biofilms richer in matrix components. This finding is of clinical importance, particularly in pediatric care, since stronger biofilms are highly associated with antimicrobial resistance, recurrent infections, and higher therapeutic failure.

Alves, Anelise Maria Costa Vasconcelos (ORCID:0000↗
DOE OSTI2022

Zap1 is required for Candida glabrata response to fluconazole

ABSTRACT The increasing prevalence of fluconazole-resistant clinical isolates of Candida spp. strongly hinders the widespread use of the drug. To tackle this problem, great efforts have been made to fully understand the fungal response to fluconazole. In this work, we show that the role of Zap1 in Candida glabrata goes beyond regulating yeast adaptation to zinc deficiency. In line with our previous observation that deletion of ZAP1 makes yeast cells more sensitive to fluconazole, we found that the mutant CgΔzap1 accumulates higher levels of the drug, which correlates well with its lower levels of ergosterol. Surprisingly, Zap1 is a negative regulator of the drug efflux transporter gene CDR1 and of its regulator, PDR1. The apparent paradox of drug accumulation in cells where genes encoding transporters relevant for drug extrusion are being overexpressed led us to postulate that their activity could be impaired. In agreement, Zap1-depleted cells present, in addition to decreased ergosterol levels, an altered composition of membrane phospholipids, which together should impact membrane function and impair the detoxification of fluconazole. Overall, our study brings to light Zap1 as an important hub in Candida glabrata response to fluconazole.

Gaspar-Cordeiro, A. (ORCID:0000000202488965)↗
DOE OSTI2021

Genetic and behavioral adaptation of Candida parapsilosis to the microbiome of hospitalized infants revealed by in situ genomics, transcriptomics, and proteomics

Background Candida parapsilosis is a common cause of invasive candidiasis, especially in newborn infants, and infections have been increasing over the past two decades. C. parapsilosis has been primarily studied in pure culture, leaving gaps in understanding of its function in a microbiome context. Results. Here, we compare five unique C. parapsilosis genomes assembled from premature infant fecal samples, three of which are newly reconstructed, and analyze their genome structure, population diversity, and in situ activity relative to reference strains in pure culture. All five genomes contain hotspots of single nucleotide variants, some of which are shared by strains from multiple hospitals. A subset of environmental and hospital-derived genomes share variants within these hotspots suggesting derivation of that region from a common ancestor. Four of the newly reconstructed C. parapsilosis genomes have 4 to 16 copies of the gene RTA3, which encodes a lipid translocase and is implicated in antifungal resistance, potentially indicating adaptation to hospital antifungal use. Time course metatranscriptomics and metaproteomics on fecal samples from a premature infant with a C. parapsilosis blood infection revealed highly variable in situ expression patterns that are distinct from those of similar strains in pure cultures. For example, biofilm formation genes were relatively less expressed in situ, whereas genes linked to oxygen utilization were more highly expressed, indicative of growth in a relatively aerobic environment. In gut microbiome samples, C. parapsilosis co-existed with Enterococcus faecalis that shifted in relative abundance over time, accompanied by changes in bacterial and fungal gene expression and proteome composition. Conclusions The results reveal potentially medically relevant differences in Candida function in gut vs. laboratory environments, and constrain evolutionary processes that could contribute to hospital strain persistence and transfer into premature infant microbiomes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

The combined application of the anti- RAS1 and anti- RIM101 2'- O MethylRNA oligomers enhances Candida albicans filamentation control

Abstract Although antisense oligomers (ASOs) have been successfully utilized to control gene expression, they have been little exploited to control Candida albicans virulence's determinants. Filamentation is an important virulence factor of C. albicans, and RAS1 and RIM101 genes are involved in its regulation. Thus, the main goal of this work was to project ASOs, based on 2'-OMethyl chemical modification, to target RAS1 and RIM101 mRNA and to validate its application either alone or in combination, to reduce Candida filamentation in different human body fluids. It was verified that both, anti-RAS1 2'OMe and anti-RIM101 2'OMe oligomers, were able to reduce the levels of RAS1 and RIM101 genes’ expression and to significantly reduce C. albicans filamentation. Furthermore, the combined application of anti-RAS1 2'OMe oligomer and anti-RIM101 2'OMe oligomer enhances the control of C. albicans filamentation in artificial saliva and urine. Our work confirms that ASOs are useful tools for research and therapeutic development on the control of candidiasis.

Barbosa, Ana↗
DOE OSTI2021

The impact of simultaneous inoculation of Pseudomonas aeruginosa, Staphylococcus aureus , and Candida albicans on rodent burn wounds

Burn wound infection often involves a diverse combination of bacterial and fungal pathogens. In this study, we characterize the mixed species burn wound infection by inoculating the burn surface with 1 × 10 3/4/5 CFU of Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans in a 1:1:1 ratio. Using the revised Walker–Mason scald burn rat model, 168 male Sprague-Dawley rats (350–450 g) subject to ~10% TBSA burn injury, with or without inoculation, were evaluated for 11 days after burn. In the wound, P. aeruginosa and S. aureus formed robust biofilms as determined by the bacterial tissue load, ~1 × 10 9 CFU/g, and expression of key biofilm genes. Interestingly, within 3 days C. albicans achieved tissue loads of ~1 × 10 6 CFU/g, but its numbers were significantly reduced beyond the limit of detection in the burn wound by day 7 in partial-thickness injuries and by day 11 in full-thickness injuries. The pathogenic biofilms contributed to burn depth progression, increased release of HMGB-1 into circulation from injured tissue, and significantly elevated the numbers of circulating innate immune cells (Neutrophils, Monocytes, and Basophils). This robust model of multi-species burn wound infection will serve as the basis for the development of new antimicrobials for combating biofilm-based wound infections.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Transcriptional and translational landscape of Candida auris in response to caspofungin

Candida auris has emerged as a serious worldwide threat by causing opportunistic infections that are frequently resistant to one or more conventional antifungal medications resulting in high mortality rates. Against this backdrop, health warnings around the world have focused efforts on understanding C. auris fungal biology and effective prevention and treatment approaches to combat this fungus. To date, there is little information about the differentially expressed genes when this fungus is treated with conventional antifungals, and caspofungin is a standard echinocandin deployed in the therapy against C. auris. In this work, we treated two distinct strains of C. auris for 24h with caspofungin, and the cellular responses were evaluated at the morphological, translational and transcriptional levels. We first observed that the echinocandin caused morphological alterations, aggregation of yeast cells, and modifications in the cell wall composition of C. auris. Transcriptomic analysis revealed an upregulation of genes related to the synthesis of the cell wall, ribosome, and cell cycle after exposure to caspofungin. Supporting these findings, the integrated proteomic analysis showed that caspofungin-treated cells were enriched in ribosome-related proteins and cell wall, especially mannoproteins. Altogether, these results provide further insights into the biology of C. auris and expands our understanding regarding the antifungal activity of caspofungin and reveal cellular targets, as the mannose metabolism, that can be further explored for the development of novel antifungals.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

CRISPR-GRIT: Guide RNAs with Integrated Repair Templates Enable Precise Multiplexed Genome Editing in the Diploid Fungal Pathogen Candida albicans

Candida albicans, an opportunistic fungal pathogen, causes severe infections in immunocompromised individuals. Limited classes and overuse of current antifungals have led to the rapid emergence of antifungal resistance. Thus, there is an urgent need to understand fungal pathogen genetics to develop new antifungal strategies. Genetic manipulation of C. albicans is encumbered by its diploid chromosomes requiring editing both alleles to elucidate gene function. Although the recent development of CRISPR-Cas systems has facilitated genome editing in C. albicans, large-scale and multiplexed functional genomic studies are still hindered by the necessity of cotransforming repair templates for homozygous knockouts. Here, we present CRISPR-GRIT (Guide RNAs with Integrated Repair Templates), a repair template-integrated guide RNA design for expedited gene knockouts and multiplexed gene editing in C. albicans. Here, we envision that this method can be used for high-throughput library screens and identification of synthetic lethal pairs in both C. albicans and other diploid organisms with strong homologous recombination machinery.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Grf10 regulates the response to copper, iron, and phosphate in Candida albicans

Abstract The pathogenic yeast, Candida albicans, and other microbes must be able to handle drastic changes in nutrient availability within the human host. Copper, iron, and phosphate are essential micronutrients for microbes that are sequestered by the human host as nutritional immunity; yet high copper levels are employed by macrophages to induce toxic oxidative stress. Grf10 is a transcription factor important for regulating genes involved in morphogenesis (filamentation, chlamydospore formation) and metabolism (adenylate biosynthesis, 1-carbon metabolism). The grf10Δ mutant exhibited resistance to excess copper in a gene dosage-dependent manner but grew the same as the wild type in response to other metals (calcium, cobalt, iron, manganese, and zinc). Point mutations in the conserved residues D302 and E305, within a protein interaction region, conferred resistance to high copper and induced hyphal formation similar to strains with the null allele. The grf10Δ mutant misregulated genes involved with copper, iron, and phosphate uptake in YPD medium and mounted a normal transcriptional response to high copper. The mutant accumulated lower levels of magnesium and phosphorus, suggesting that copper resistance is linked to phosphate metabolism. Our results highlight new roles for Grf10 in copper and phosphate homeostasis in C. albicans and underscore the fundamental role of Grf10 in connecting these with cell survival.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Structural analysis of wild-type and Val120Thr mutant Candida boidinii formate dehydrogenase by X-ray crystallography

Candida boidinii NAD + -dependent formate dehydrogenase (CbFDH) has gained significant attention for its potential application in the production of biofuels and various industrial chemicals from inorganic carbon dioxide. The present study reports the atomic X-ray crystal structures of wild-type CbFDH at cryogenic and ambient temperatures, as well as that of the Val120Thr mutant at cryogenic temperature, determined at the Turkish Light Source ‘Turkish DeLight’. The structures reveal new hydrogen bonds between Thr120 and water molecules in the active site of the mutant CbFDH, suggesting increased stability of the active site and more efficient electron transfer during the reaction. Further experimental data is needed to test these hypotheses. Collectively, these findings provide invaluable insights into future protein-engineering efforts that could potentially enhance the efficiency and effectiveness of CbFDH.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Genome Sequence and Analysis of the Flavinogenic Yeast Candida membranifaciens IST 626

The ascomycetous yeast Candida membranifaciens has been isolated from diverse habitats, including humans, insects, and environmental sources, exhibiting a remarkable ability to use different carbon sources that include pentoses, melibiose, and inulin. In this study, we isolated four C. membranifaciens strains from soil and investigated their potential to overproduce riboflavin. C. membranifaciens IST 626 was found to produce the highest concentrations of riboflavin. The volumetric production of this vitamin was higher when C. membranifaciens IST 626 cells were cultured in a commercial medium without iron and when xylose was the available carbon source compared to the same basal medium with glucose. Supplementation of the growth medium with 2 g/L glycine favored the metabolization of xylose, leading to biomass increase and consequent enhancement of riboflavin volumetric production that reached 120 mg/L after 216 h of cultivation. To gain new insights into the molecular basis of riboflavin production and carbon source utilization in this species, the first annotated genome sequence of C. membranifaciens is reported in this article, as well as the result of a comparative genomic analysis with other relevant yeast species. A total of 5619 genes were predicted to be present in C. membranifaciens IST 626 genome sequence (11.5 Mbp). Among them are genes involved in riboflavin biosynthesis, iron homeostasis, and sugar uptake and metabolism. This work put forward C. membranifaciens IST 626 as a riboflavin overproducer and provides valuable molecular data for future development of superior producing strains capable of using the wide range of carbon sources, which is a characteristic trait of the species.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

The role of non-standard translation in Candida albicans pathogenesis

ABSTRACT Candida albicans typically resides in the human gastrointestinal tract and mucosal membranes as a commensal organism. To adapt and cope with the host immune system, it has evolved a variety of mechanisms of adaptation such as stress-induced mutagenesis and epigenetic regulation. Niche-specific patterns of gene expression also allow the fungus to fine-tune its response to specific microenvironments in the host and switch from harmless commensal to invasive pathogen. Proteome plasticity produced by CUG ambiguity, on the other hand is emerging as a new layer of complexity in C. albicans adaptation, pathogenesis, and drug resistance. Such proteome plasticity is the result of a genetic code alteration where the leucine CUG codon is translated mainly as serine (97%), but maintains some level of leucine (3%) assignment. In this review, we dissect the link between C. albicans non-standard CUG translation, proteome plasticity, host adaptation and pathogenesis. We discuss published work showing how this pathogen uses the fidelity of protein synthesis to spawn novel virulence traits.

Bezerra, Ana Rita (ORCID:0000000346131711)↗
DOE OSTI2021

Adaptation to the dietary sugar D-tagatose via genome instability in polyploid Candida albicans cells

The opportunistic fungal pathogen Candida albicans undergoes an unusual parasexual cycle wherein diploid cells mate to form tetraploid cells that can generate genetically diverse progeny via a nonmeiotic program of chromosome loss. The genetic diversity afforded by parasex impacts clinically relevant features including drug resistance and virulence, and yet the factors influencing genome instability in C. albicans are not well defined. To understand how environmental cues impact genome instability, we monitored ploidy change following tetraploid cell growth in a panel of different carbon sources. We found that growth in one carbon source, D-tagatose, led to high levels of genomic instability and chromosome loss in tetraploid cells. This sugar is a stereoisomer of L-sorbose which was previously shown to promote karyotypic changes in C. albicans. However, while expression of the SOU1 gene enabled utilization of L-sorbose, overexpression of this gene did not promote growth in D-tagatose, indicating differences in assimilation of the two sugars. In addition, genome sequencing of multiple progenies recovered from D-tagatose cultures revealed increased relative copy numbers of chromosome 4, suggestive of chromosome-level regulation of D-tagatose metabolism. Together, these studies identify a novel environmental cue that induces genome instability in C. albicans, and further implicate chromosomal changes in supporting metabolic adaptation in this species.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Antimicrobial activity of peptoids against Metallo-β-lactamase-producing Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa , and other WHO priority pathogens, including Candida auris

Abstract Aims The World Health Organization has identified ESKAPE bacteria and Candida auris as priority pathogens, emphasizing an urgent need for novel antimicrobials to combat them. This study aimed to explore the therapeutic potential of antimicrobial peptidomimetics, specifically peptoids with sequence-specific N-substituted glycines, against ESKAPEE pathogens, including metallo-β-lactamase (MBL) producers, as well as C. auris strains. Methods and results This study evaluated activity of the peptoids against the multidrug-resistant priority pathogens. The peptoid TM8 (with an N-decyl alkyl chain) demonstrated a geometric mean minimum inhibitory concentration (MIC) of 7.8 μg ml−1 against MBL-producing bacteria, and 5.5 μg ml−1 against C. auris. TM8 showed synergy with ciprofloxacin, enhancing its effectiveness 4-fold against NDM-1-producing Klebsiella pneumoniae. No antagonism was seen when TM8 was used with either conventional antibiotics or antifungals. Peptoids that had therapeutic indices below 3 were generally more hydrophobic, due to either alkyl chains or bromine. Scanning electron microscopy and live-dead staining assay on peptoid-treated C. auris confirmed morphological changes and killing activity, respectively. Furthermore, the peptoid could effectively inhibit biofilm formation by C. auris. Conclusion Peptoids demonstrated antibacterial activity against ESKAPEE, particularly against MBL-producing Gram-negative bacteria. Additionally, they exhibited antifungal and anti-biofilm activities against C. auris strains.

Biotechnology & Applied Microbiology↗
DOE OSTI2024

Molecular and Epidemiological Investigation of Fluconazole-resistant Candida parapsilosis —Georgia, United States, 2021

Abstract Background Reports of fluconazole-resistant Candida parapsilosis bloodstream infections are increasing. We describe a cluster of fluconazole-resistant C parapsilosis bloodstream infections identified in 2021 on routine surveillance by the Georgia Emerging Infections Program in conjunction with the Centers for Disease Control and Prevention. Methods Whole-genome sequencing was used to analyze C parapsilosis bloodstream infections isolates. Epidemiological data were obtained from medical records. A social network analysis was conducted using Georgia Hospital Discharge Data. Results Twenty fluconazole-resistant isolates were identified in 2021, representing the largest proportion (34%) of fluconazole-resistant C parapsilosis bloodstream infections identified in Georgia since surveillance began in 2008. All resistant isolates were closely genetically related and contained the Y132F mutation in the ERG11 gene. Patients with fluconazole-resistant isolates were more likely to have resided at long-term acute care hospitals compared with patients with susceptible isolates (P = .01). There was a trend toward increased mechanical ventilation and prior azole use in patients with fluconazole-resistant isolates. Social network analysis revealed that patients with fluconazole-resistant isolates interfaced with a distinct set of healthcare facilities centered around 2 long-term acute care hospitals compared with patients with susceptible isolates. Conclusions Whole-genome sequencing results showing that fluconazole-resistant C parapsilosis isolates from Georgia surveillance demonstrated low genetic diversity compared with susceptible isolates and their association with a facility network centered around 2 long-term acute care hospitals suggests clonal spread of fluconazole-resistant C parapsilosis. Further studies are needed to better understand the sudden emergence and transmission of fluconazole-resistant C parapsilosis.

Misas, Elizabeth (ORCID:0000000162437716)↗
DOE OSTI2021

Population genomics of the pathogenic yeast Candida tropicalis identifies hybrid isolates in environmental samples

Candida tropicalis is a human pathogen that primarily infects the immunocompromised. Whereas the genome of one isolate, C. tropicalis MYA-3404, was originally sequenced in 2009, there have been no large-scale, multi-isolate studies of the genetic and phenotypic diversity of this species. Here, we used whole genome sequencing and phenotyping to characterize 77 isolates of C. tropicalis from clinical and environmental sources from a variety of locations. We show that most C. tropicalis isolates are diploids with approximately 2–6 heterozygous variants per kilobase. The genomes are relatively stable, with few aneuploidies. However, we identified one highly homozygous isolate and six isolates of C. tropicalis with much higher heterozygosity levels ranging from 36–49 heterozygous variants per kilobase. Our analyses show that the heterozygous isolates represent two different hybrid lineages, where the hybrids share one parent (A) with most other C. tropicalis isolates, but the second parent (B or C) differs by at least 4% at the genome level. Four of the sequenced isolates descend from an AB hybridization, and two from an AC hybridization. The hybrids are MTLa/α heterozygotes. Hybridization, or mating, between different parents is therefore common in the evolutionary history of C. tropicalis. The new hybrids were predominantly found in environmental niches, including from soil. Hybridization is therefore unlikely to be associated with virulence. In addition, we used genotype-phenotype correlation and CRISPR-Cas9 editing to identify a genome variant that results in the inability of one isolate to utilize certain branched-chain amino acids as a sole nitrogen source.

59 BASIC BIOLOGICAL SCIENCES↗