Sharon L. Reed

University of California, San Diego

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Ken Hirata

University of California, San Diego

Xuchu Que

University of California, San Diego

James H. McKerrow

University of California, San Diego

Lars Eckmann

University of California, San Diego

Anjan Debnath

Center for Discovery

Robert T. Schooley

University of California, San Diego

Randy Taplitz

City Of Hope National Medical Center

Martin Hoenigl

Medical University of Graz

B E Torian

Center for Infectious Disease Research

Ronald W. McLawhon

University of California, San Diego

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University of California, San Diego

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University of California, San Francisco

University of California San Diego Medical Center

UC San Diego Health System

University of California System

Scripps Research Institute

Scripps Institution of Oceanography

National Institutes of Health

Scripps (United States)

Centers for Disease Control and Prevention

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Synthesis and Evaluation of Oxyguanidine Analogues of the Cysteine Protease Inhibitor WRR-483 against Cruzain

ACS Medicinal Chemistry Letters (2015)

Brian Jones A. Tochowicz Yinyan Tang Michael D. Cameron Laura‐Isobel McCall

A series of oxyguanidine analogues of the cysteine protease inhibitor WRR-483 were synthesized and evaluated against cruzain, the major cysteine protease of the protozoan parasite Trypanosoma cruzi. Kinetic analyses of these analogues indicated that they have comparable potency to previously prepared vinyl sulfone cruzain inhibitors. Co-crystal structures of the oxyguanidine analogues WRR-666 (4) and WRR-669 (7) bound to cruzain demonstrated different binding interactions with the cysteine protease, depending on the aryl moiety of the P1' inhibitor subunit. Specifically, these data demonstrate that WRR-669 is bound noncovalently in the crystal structure. This represents a rare example of noncovalent inhibition of a cysteine protease by a vinyl sulfone inhibitor.

Cysteine protease

Moiety

Cysteine Proteinase Inhibitors

Protease inhibitor (pharmacology)

10.1021/acsmedchemlett.5b00336

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Citations (38)

Bronchoalveolar lavage Aspergillus Galactomannan lateral flow assay versus Aspergillus-specific lateral flow device test for diagnosis of invasive pulmonary Aspergillosis in patients with hematological malignancies

Journal of Infection (2018)

Jeffrey D. Jenks Sanjay R. Mehta Randy Taplitz Nancy Law Sharon L. Reed

Galactomannan

10.1016/j.jinf.2018.10.014

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Citations (52)

Direct Detection of Beta-Lactamase Mediated Antibiotic Resistance In Clinical Specimens

American Journal of Clinical Pathology (2021)

Nick Bevins Raymond T. Suhandynata Andrés Mauricio Caraballo‐Rodríguez Sharon L. Reed Pieter C. Dorrestein

Abstract Antibiotic resistance mediated by beta-lactamase enzyme expression is a serious and growing threat. The typical workflow in a clinical microbiology lab leading to identification of beta-lactamase expressing organisms typically requires 48 to 72 hours and involves multiple manual steps. Empiric treatment with potentially ineffective antibiotics often occurs before susceptibility testing results are available. Objective: The objective of our study was to determine if beta-lactamase activity could be detected in clinical urine samples to provide same-day rule-out of select empiric treatment regimens for urinary tract infections. Methods: We acquired urine samples from 40 patients with extended spectrum beta-lactamase expressing (ESBL) infections and 100 patients without ESBL infection as determined by standard culture and sensitivity methods. These samples were incubated with spiked beta-lactam antibiotics susceptible to ESBL degradation (ceftriaxone, cefazolin, and oxacillin) or resistant to ESBL degradation (meropenem). Results: Hydrolysis of spiked drug was detected after a 4 hour incubation with either liquid-chromatography mass-spectrometry (LC-MS) or matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) methods. A 100 to 1000 fold reductions in measured concentrations of spiked ceftriaxone, cefazolin, or oxacillin were observed with LC-MS or MALDI-TOF methods for all 40 ESBL containing specimens and unchanged concentrations of spiked drug were observed in all 100 non-ESBL containing specimens. Concentration of spiked meropenem (resistant to ESBL degradation) were unchanged in all specimens after incubation regardless of ESBL status. Addition of a beta-lactamase inhibitor prevented ESBL degradation of ceftriaxone, cefazolin, and oxacillin demonstrating that beta-lactamase activity (and not another method of drug degradation or signal masking) is being detected. Incubation times as long as 24 hours (to determine method specificity) and as short as 30 minutes (to determine method sensitivity) all showed robust discrimination between ESBL-containing and non-ESBL containing specimens. Conclusion: Our results demonstrate that beta-lactamase activity can be robustly detected in urine samples days before culture and susceptibility results could be available. Clinical utilization of the assay described would enable clinicians to reduce ineffective empiric treatment of ESBL urinary infections.

Cefazolin

Beta-lactamase

10.1093/ajcp/aqab189.002

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Amebosis e infección por amiba de vida libre

Rosa-M. Andrade Sharon L. Reed

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Molecular and cellular characterization of the 29-kilodalton peripheral membrane protein of Entamoeba histolytica: differentiation between pathogenic and nonpathogenic isolates

Infection and Immunity (1992)

Sharon L. Reed B M Flores Mark A. Batzer Markus Stein Virginia L. Stroeher

To further characterize the 29-kDa surface antigen of Entamoeba histolytica, we analyzed the complete nucleotide sequence and compared the immunoreactivity of this antigen in pathogenic and nonpathogenic strains. Five cDNA clones (one 1.0-kb full-length clone, designated p13, and four partial-length clones) encoding the antigen were analyzed for allelic variation. Comparison of the nucleotide sequences revealed several single-nucleotide substitutions in all five cDNAs, two of which resulted in amino acid differences. Localization of the antigen to the amebic surface in a previous report (B. E. Torian, B. M. Flores, V. L. Stroeher, F. S. Hagen, and W. E. Stamm, Proc. Natl. Acad. Sci. USA 87:6358-6362, 1990) was corroborated by transmission electron microscopy showing colloidal gold particles on the surface of the trophozoites. Computer analysis of the deduced amino acid sequence predicted that the protein encoded by p13 was a hydrophilic peripheral membrane protein, and these data were confirmed by a Triton X-114 membrane extraction showing the presence of the 29-kDa antigen primarily in the aqueous phase of the detergent partition. Monoclonal antibodies to a fusion peptide differentiated between pathogenic and nonpathogenic clinical strains of E. histolytica in immunoblots. Although no immunoreactive epitopes were detected on nonpathogenic strains, Northern (RNA) analysis and DNA-DNA hybridization with a 700-bp cDNA probe demonstrated that mRNA and the gene encoding the 29-kDa surface antigen were present in both pathogenic and nonpathogenic clinical isolates.

10.1128/iai.60.2.542-549.1992

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Citations (41)

Longitudinal Monitoring of SARS-CoV-2 IgM and IgG Seropositivity to Detect COVID-19

The Journal of Applied Laboratory Medicine (2020)

Raymond T. Suhandynata Melissa Hoffman Michael J. Kelner Ronald W. McLawhon Sharon L. Reed

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a novel beta-coronavirus that has recently emerged as the cause of the 2019 coronavirus pandemic (COVID-19). Polymerase chain reaction (PCR) based tests are optimal and recommended for the diagnosis of an acute SARS-CoV-2 infection. Serology tests for viral antibodies provide an important tool to diagnose previous exposure to the virus. Here we evaluate the analytical performance parameters of the Diazyme SARS-CoV-2 IgM/IgG serology assays and describe the kinetics of IgM and IgG seroconversion observed in patients with PCR-confirmed COVID-19 who were admitted to our hospital. Methods We validated the performance of the Diazyme assay in 235 presumed SARS-CoV-2 negative subjects to determine specificity. Subsequently, we evaluated the SARS-CoV-2 IgM and IgG seroconversion of 54 PCR-confirmed COVID-19 patients and determined sensitivity of the assay at three different timeframes. Result Sensitivity and specificity for detecting seropositivity at ≥15 days following a positive SARS-CoV-2 PCR result, was 100.0% and 98.7% when assaying for the panel of IgM and IgG. The median time to seropositivity observed for a reactive IgM and IgG result from the date of a positive PCR was 5 days (IQR: 2.75–9 days) and 4 days (IQR: 2.75–6.75 days), respectively. Conclusions Our data demonstrate that the Diazyme IgM/IgG assays are suited for the purpose of detecting SARS-CoV-2 IgG and IgM in patients with suspected SARS-CoV-2 infections. For the first time, we report longitudinal data showing the evolution of seroconversion for both IgG and IgM in a cohort of acutely ill patients in the United States. We also demonstrate a low false positive rate in patients who were presumed to be disease free.

Seroconversion

Immunoglobulin M

Coronavirus

10.1093/jalm/jfaa079

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Genome of the pathogen Porphyromonas gingivalis recovered from a biofilm in a hospital sink using a high-throughput single-cell genomics platform

Genome Research (2013)

Jeffrey S. McLean Mary‐Jane Lombardo Michael G. Ziegler Mark Novotny Joyclyn Yee-Greenbaum

Although biofilms have been shown to be reservoirs of pathogens, our knowledge of the microbial diversity in biofilms within critical areas, such as health care facilities, is limited. Available methods for pathogen identification and strain typing have some inherent restrictions. In particular, culturing will yield only a fraction of the species present, PCR of virulence or marker genes is mainly focused on a handful of known species, and shotgun metagenomics is limited in the ability to detect strain variations. In this study, we present a single-cell genome sequencing approach to address these limitations and demonstrate it by specifically targeting bacterial cells within a complex biofilm from a hospital bathroom sink drain. A newly developed, automated platform was used to generate genomic DNA by the multiple displacement amplification (MDA) technique from hundreds of single cells in parallel. MDA reactions were screened and classified by 16S rRNA gene PCR sequence, which revealed a broad range of bacteria covering 25 different genera representing environmental species, human commensals, and opportunistic human pathogens. Here we focus on the recovery of a nearly complete genome representing a novel strain of the periodontal pathogen Porphyromonas gingivalis ( P. gingivalis JCVI SC001) using the single-cell assembly tool SPAdes. Single-cell genomics is becoming an accepted method to capture novel genomes, primarily in the marine and soil environments. Here we show for the first time that it also enables comparative genomic analysis of strain variation in a pathogen captured from complex biofilm samples in a healthcare facility.

Human pathogen

10.1101/gr.150433.112

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Citations (62)

Bacteriophage Treatment in a Lung Transplant Recipient

The Journal of Heart and Lung Transplantation (2018)

Saima Aslam Gordon Yung Jennifer M. Dan Sharon L. Reed Muriel Lefebvre

10.1016/j.healun.2018.01.376

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Citations (18)

Gonococcal Meningitis Diagnosed by DNA Amplification: Case Report and Review of the Literature

AIDS Patient Care and STDs (2007)

Edward R. Cachay William C. Mathews Sharon L. Reed Mark A. Swancutt Joshua Fierer

We report a case of gonococcal meningitis diagnosed by DNA amplification. A 47-year old man presented with a 4-day history of asymmetric painful swelling of his ankles and wrists, and skin rash. He had sex with men only but was HIV negative. Headache and photophobia led to a cerebrospinal fluid (CSF) examination that revealed meningitis. Cultures were negative but we detected Neisseria gonorrhoeae in his urine and CSF using a GC/chlamydia DNA amplification assay. The patient was discharged without sequela after 14 days of intravenous ceftriaxone.

Photophobia

Sequela

Neisseria gonorrhoeae

10.1089/apc.2006.0049

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Citations (10)

Detection of HIV-1 in Entamoeba histolytica without evidence of transmission to human cells

AIDS (1991)

Margaret Brown Sharon L. Reed Jay A. Levy Michael P. Busch James H. McKerrow

Intestinal protozoa like Entamoeba histolytica and Giardia lamblia have been proposed as vectors or cofactors in the development of AIDS. To determine whether these protozoa could transmit HIV, laboratory strains of protozoa were cocultured with cells chronically infected by a highly replicative strain of HIV-1. Entamoeba histolytica, but not Giardia lamblia, took up virus. Immunologically detectable HIV-1 was present in the amebae up to 48 h after exposure to infected cells, but this virus could not be transferred to uninfected human cells. Amebae isolated directly from two HIV-infected individuals were also found to be positive for HIV-1. After lysis of these protozoa and coculture with uninfected peripheral blood mononuclear cells, no transfer of virus to the human cells was observed.

Giardia lamblia

Giardia

10.1097/00002030-199101000-00014

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Citations (13)