About

Annelise E. Barron is the W.M. Keck Associate Professor of Bioengineering at Stanford University. Her research focuses on the study, biomimicry, and upregulation of natural human host defense peptides, particularly LL-37, which plays a crucial role in innate immune defense against pathogens. Her work explores the molecular biophysics, anti-infective, and immunomodulatory mechanisms of LL-37, including its role in preventing Alzheimer's and Parkinson's diseases by binding to amyloid peptides and inhibiting fibril formation. Her lab investigates infectious mechanisms of neurological diseases and develops biostable peptoid mimics of LL-37 as therapeutics to combat antibiotic-resistant infections, with particular interest in neurological, eye, ear, sinus, and lung infections. Additionally, her research extends to understanding the pathogenic mechanisms of COVID-19, especially regarding innate immunity dysregulation and its impact on vulnerable populations such as diabetics and those with poor metabolic health. Dr. Barron is trained as a chemical and biological engineer, with degrees from the University of Washington and UC Berkeley, and postdoctoral experience at UCSF and Soane BioSciences. She has served on the faculty at Stanford since 2007, after a decade at Northwestern University, and has received numerous awards including the NIH Pioneer Award, the Oskar Fischer Award, and the PECASE. She has over 177 publications, a high H-index, and is involved in biotechnology advisory roles.

Research topics

• Biology
• Chemistry
• Biochemistry
• Bioinformatics
• Microbiology
• Psychology
• Pathology
• Medicine
• Neuroscience
• Stereochemistry
• Immunology
• Combinatorial chemistry
• Organic chemistry

Selected publications

• Peptoid-based antimicrobial strategies against polymyxin-resistant Gram-negative bacteria

  Journal of Applied Microbiology · 2026-04-01

  articleOpen access

  AIMS: Polymyxins remain the mainstay antibiotic for the treatment of infections caused by multidrug-resistant bacteria. However, with the increase in the use of polymyxins, the simultaneous rise of polymyxin-resistance cases has been another global threat, necessitating the need for novel therapeutic strategies. This work aimed to evaluate the antibacterial activity of cationic peptoids against polymyxin-resistant bacteria of global priority. METHODS AND RESULTS: Three paired polymyxin-sensitive/polymyxin-resistant strains were included, along with two clinical isolates and one reference strain. Out of nine cationic peptoids, TM8 showed the most potent activity against the polymyxin-resistant bacteria with a geometric mean minimum inhibitory concentration (MIC) of 15.6 μg mL-1. The MIC of TM8 was 2-fold higher in polymyxin-resistant cases. TM8 synergized with colistin, rifampicin, and ciprofloxacin in polymyxin-resistant bacteria with reductions in MIC of antibiotics ranging from 8- to 64-fold. Enterobacter cloacae did not develop resistance to TM8 upon repeated subpassage at its sub-MIC, whereas it evolved to resist ciprofloxacin by sixty-four-fold under the same conditions. A concentration-dependent membrane-disruptive potential activity was noted in flow cytometry using live-dead staining. The impact of monovalent cations was small (≤2-fold change), while in the presence of divalent cations, the MIC of TM8 increased up to 4-fold. CONCLUSION: This study presents TM8 as a potential candidate antimicrobial against polymyxin-resistant bacteria. Further studies are recommended focusing on safety, pharmacokinetics, and pharmacodynamics of this compound.

  PublisherDOI

• Investigation of Regulation and Binding Patterns of the Human Cathelicidin Peptide LL-37 in Complexation with Nucleic Acids, and its Impact on Neutrophil Extracellular Traps

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-11

  articleOpen accessSenior authorCorresponding

  The human cathelicidin host defense peptide LL-37 forms complexes with nucleic acids that can have either beneficial or detrimental health effects. We suggest that these differential impacts are directly connected to dsDNA binding by LL-37 and to complex formation between protomers. Here, we show using phage λ DNA that LL-37 binds non-specifically to dsDNA, condensing it, followed by complex formation between LL-37 peptides. We find that complex formation is concentration-dependent, with low LL-37 amounts yielding loosely aggregated DNA structures, while higher LL-37 concentrations lead to well-defined, disc-like structures of about 150 nm in diameter. The condensation of the nucleic acids, which causes a loss of the characteristic B-DNA features, results from interactions of the phosphodiester backbone with protonated amino acid side chains of the peptide at physiological pH, predominantly in A-T rich sequences of the nucleic acid. However, in our studies, electrostatic interactions did not appear to be the driving force for complexation, but rather we found the α-helical structure of the peptide with its amphipathic and hydrophobic surfaces to be essential. Further, we show that LL-37 also interacts with nucleic acids from neutrophil extracellular traps (NETs) in a concentration-dependent way, causing a reduction in NET aggregate area, which may offer new biophysical insights into diseases such as systemic lupus erythematosus (SLE), which involve slower-than-normal NET clearance. Our results indicate the key importance of LL-37 expression levels for regulation of the innate immune system for optimal human health, since the relative amounts of expressed LL-37 present to interact with extracellular DNA will determine the extent to which the DNA can be condensed, which in turn will affect the ability of the body to clear the NETs before they can cause inflammatory conditions.

  PublisherDOI

• Identification of gingipains in glioblastoma tumors and evidence that <i>P. gingivalis</i> infection drives IL-6 and PD-L1 expression in glioma cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-14 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Glioblastoma multiforme (GBM), a highly aggressive brain tumor that accounts for approximately 60% of all gliomas and 48% of primary central nervous system malignancies, is incurable and poorly understood, with a median survival of only 15 months after diagnosis. Thus, there is an urgent need to understand GBM pathogenesis in order to develop an effective treatment. Recent research has revealed frequent Alzheimer’s disease (AD) pathology in the brains of patients with GBM, i.e. , amyloid beta (Aβ) and hyperphosphorylated tau (pTau), indicating that GBM and AD may share some unknown environmental risk. Since chronic periodontitis (CP), and specifically Porphyromonas gingivalis ( P. gingivalis) , a keystone bacterial pathogen in CP, have emerged as risk factors for both AD and GBM, we investigated whether P. gingivalis gingipain virulence factors could be identified in GBM tissue samples and whether P. gingivalis infection affects glioma cell behavior. Using immunohistochemistry on tissue microarrays (70 GBM cores from 35 patients; 34 cerebral tissue cores from 17 patients), we quantified the presence of arginine-gingipain B (RgpB) and lysine-gingipain (Kgp) antigens. Both gingipains showed significantly elevated staining in GBM samples compared to controls (**p &lt; .01, ****p &lt; .0001, respectively), with Kgp levels notably higher than RgpB within GBM tissue (****p &lt; .0001). In functional assays using U251 glioma cells, P. gingivalis infection induced robust, dose-dependent IL-6 secretion (peaking at MOI 5), increased PD-L1 expression by 30% (*p = .036), and significantly enhanced cell invasiveness (**p &lt; .01) in a viability-dependent manner. These findings demonstrate that P. gingivalis gingipains are present at elevated levels in GBM tissue and that P. gingivalis infection reprograms glioma cells to adopt an immunosuppressive, invasive phenotype through upregulation of the IL-6/PD-L1 axis, suggesting a potential microbial contribution to GBM pathogenesis and immune evasion. Key points Glioblastoma multiforme (GBM) patients have frequent Alzheimer’s disease (AD) neuropathological changes in the tumor-adjacent cortex, indicating that GBM tumors may share some environmental risk factors with AD. This study identifies gingipain antigens in GBM tissue samples at significantly elevated levels compared to healthy controls, suggesting that P. gingivalis infection may be an environmental risk factor for both AD and GBM. In in vitro experiments, P. gingivalis infection of the human glioma cell line U251 upregulated IL-6 secretion and PD-L1 expression, and significantly increased cell invasiveness compared to uninfected cells.

  PublisherOA PDFDOI

• The dysregulation of innate immunity by <i>Porphyromonas gingivalis</i> in the etiology of Alzheimer's disease

  Journal of Internal Medicine · 2025-12-22

  articleOpen access1st authorCorresponding

  The etiology of Alzheimer's disease (AD) remains under active debate. In this perspective, we explore the hypothesis that a primarily infection-caused chronic dysregulation and weakening of human innate immunity via the underexpression, degradation, and inactivation of innate immune proteins necessary for direct antimicrobial effects and regulation of host defense and autophagy could lead to AD. Key evidence relates to the fact that important innate immune proteins such as LL-37-which can bind Aβ and block amyloid formation-as well as Apolipoprotein E, antiviral interferons, and TNF-α can be degraded and deactivated by enzymes produced by the common oral anaerobic pathogen Porphyromonas gingivalis (Pg). Pg produces numerous virulence factors; of particular importance for AD are Pg's gingipain cysteine proteases. Deleterious effects of chronic Pg infection and gingipains include a systemic downregulation and paralysis of the interferon response, particularly the antiviral interferon-lambda response, which enables replication of endemic herpesviruses. The result is a chronic, low-level viral infectious assault on gut, nerves, and brain causing the production of Aβ antimicrobial peptides, accumulation of Aβ plaques, phosphorylation of Tau, progressive neuroinflammation, and neurodegeneration. The resultant innate immune system dysregulation, as an AD etiology, ties together the well-known amyloid cascade hypothesis and the infectious theory of AD into a unified explanation of the pathology and cause of AD. If this theory holds true, it suggests preventative approaches: (1) test for and eradicate Pg from oral flora, and/or directly deactivate the gingipains; and (2) reduce Herpesvirus exacerbations by the use of antiviral drugs and/or vaccines (e.g., Bacillus Calmette-Guérin).

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• Local enhancement of cationic charge density via polyamine side chain incorporation improves the selectivity of antimicrobial peptoids

  European Journal of Medicinal Chemistry · 2025-07-02 · 2 citations

  article
  PublisherDOI

• Novel Antifungal Strategies for Airway Mycosis

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  article

  Abstract Introduction: Chronic diseases like asthma have been linked to airway mycosis, the non-invasive growth of fungi along airway epithelium. The fungi commonly linked to asthma and invasive disease include yeasts, specifically, Candida spp. and molds specifically, Aspergillus spp. Conventional antifungals are effective in asthma and disseminated fungal disease, but treatment failures occur frequently. Recently, a new class of antifungals possessing unique peptoid-based chemistry has been shown to be effective against bacteria, but their efficacy against fungal pathogens has not been studied. We hypothesized that combinations of standard antifungals with synergistic activity or peptoids will kill resistant fungi linked to invasive disease and airway mycosis. Methods: In vitro fungistasis assay. WST-1 prepared in RPMI 1640 with terbinafine, voriconazole, itraconazole, and amphotericin B and the peptoid agent TM4 in two-fold serial concentrations were added microtiter plates. Next, 80 spores or yeast cells of A. niger, C. albicans, and C. auris, were added and germinated for four hours after which absorbance readings were obtained to quantify fungal growth. Minimum Inhibitory Concentrations (MICs in μg/ml) were determined by extrapolation of absorbance readings. The above steps were repeated for dual therapy combinations (to determine additive, synergistic, and antagonistic effects) and for peptoids. In vivo experiments. Peptoids were studied for efficacy in vivo in dexamethasone-treated C57BL/6 female mice after intranasal challenge with A. niger. Seven days post-infection, lungs were removed and plated on antibiotic free Sabouraud agar plates at room temperature. Lung CFU were enumerated within 48 hours. Results: In vitro assay. Terbinafine was effective against A. niger and C. albicans (MICs of 0.313 and 0.156, respectively). Voriconazole and itraconazole were efficacious for A. niger (MIC: 0.0625) but ineffective for C. auris (MIC: 1.25). For C. albicans, the itraconazole MIC was 0.078 and for voriconazole the MIC was 0.156. Amphotericin B's MIC was 0.313 for A. niger, 0.078 for C. albicans, and 0.313 for C. auris. In contrast, peptoid TM4 produced the same results for A. niger, C. albicans, and C. auris with MICs of 8, 4, and 8, respectively. Only peptoids and amphotericin B were found to be fungicidal; other antifungals were fungistatic. In vivo experiments. After treatment with TM4 three hours post infection, lung CFUs were significantly decreased compared to A. niger group alone (p-value of 0.027). Conclusions: Standard antifungals ranged in effectiveness in a fungal species-dependent manner. Peptoids are more promising than amphotericin B for treating life-threatening fungal disease and deserve additional study.

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• Targeting intracellular of populations <i>Pseudomonas aeruginosa</i> with peptide-mimetic therapies: individual efficacy and synergistic rescue of obsolete antibiotics

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-26

  preprintOpen access

  Abstract Pseudomonas aeruginosa is a leading cause of human infections, with current treatment options severely limited by high levels of antimicrobial resistance. Historically considered to be an extracellular pathogen, recent evidence has emerged that P. aeruginosa is able to survive and replicate within human cells. These intracellular niches present an additional clinical challenge and may serve as bacterial reservoirs associated with chronic infections that are particularly difficult to eradicate. Here we describe the application of a novel peptide-based therapeutic against recalcitrant populations of bacteria residing within lung epithelial cells. This antimicrobial “peptoid” is able to target intracellular bacteria without harming host cells. In addition, we have shown that peptoid TM5 exhibits synergy with three antibiotics that otherwise have low efficacy against P. aeruginosa , effectively rescuing drugs that have become clinically obsolete. These synergistic combination therapies are also capable of reducing intracellular bacterial reservoirs, opening the door for potential new strategies against chronic P. aeruginosa infections.

  PublisherOA PDFDOI

• Evaluation of the Synergistic Activity of Antimicrobial Peptidomimetics or Colistin Sulphate with Conventional Antifungals Against Yeasts of Medical Importance

  Journal of Fungi · 2025-05-12

  articleOpen access

  With rising multidrug-resistant yeast pathogens, conventional antifungals are becoming less effective, urging the need for adjuvants that enhance their activity at lower doses. This study evaluated the synergistic activity of antimicrobial peptidomimetics (TM8 and RK758) or colistin sulphate in combination with conventional antifungals against Candida albicans, C. tropicalis, C. parapsilosis, Meyerozyma guilliermondii, Nakaseomyces glabratus, Pichia kudriavzevii and Kluyveromyces marxianus, and Candidozyma auris using the checkerboard microdilution test. RK758 was synergistic with fluconazole in 78% of isolates, with the remaining 22% of isolates still showing partial synergy; it showed synergy with amphotericin B in 56% of isolates, and with caspofungin, 78% of isolates exhibited either synergy or partial synergy. TM8 showed synergy with fluconazole in 44% (with partial synergy in another 44%) of isolates, with amphotericin B in 67% of isolates, and with caspofungin in 44% (with partial synergy in another 44%) of isolates. Colistin with fluconazole or caspofungin exhibited synergy or partial synergy in 56% of the isolates. No antagonism was observed in any of the combinations. Additionally, a time-kill assay further demonstrated synergistic activity between fluconazole and TM8 or RK758. The effects of these peptidomimetics on cell membrane integrity were demonstrated in an ergosterol binding assay, supported by SYTOX Green and cellular leakage assays, both indicating a lytic effect. These results suggest that peptidomimetics can synergise with conventional antifungals, offering a potential strategy for combination therapy against yeast infections. The membrane lytic activity of the peptidomimetics likely plays a role in their synergistic interaction with antifungals, thereby enhancing the antimicrobial activities of both compounds at sub-MIC levels.

  PublisherOA PDFDOI

• Time-resolved phenotyping at subcellular resolution reveals shared principles and key trade-offs across antimicrobial peptide activities

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-10 · 1 citations

  preprintOpen access

  ABSTRACT Cationic antimicrobial peptides are a large family of host defense molecules with diverse sequences and structures. Here, we present a computational and experimental pipeline for time-resolved quantification of both membrane-permeabilizing and intracellular effects in Escherichia coli . Applying this pipeline to 12 diverse natural peptides and synthetic peptidomimetics uncovers shared antimicrobial activities, but with different kinetics, forming two classes. With class I peptides, growth arrest is abrupt and predominantly coupled with inner membrane permeabilization and ribosome/DNA reorganization. However, membrane permeabilization leads to rapid peptide absorption by the first exposed bacterial cells, resulting in low efficacy against dense populations. With class II peptides, ribosome/DNA reorganization and growth inhibition occur more gradually, as inner membrane permeabilization is either absent or delayed. This is offset by slower intracellular peptide uptake and greater efficacy against high cell densities. These kinetic differences reveal functional trade-offs between classes that have major immunological and therapeutic implications.

  PublisherOA PDFDOI

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

  Journal of Applied Microbiology · 2025-02-11 · 4 citations

  articleOpen access

  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.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01AI072666

  NIH · $1.8M · 2012

• NIH Grant R01HL067984

  NIH · $2.5M · 2011

• NIH Grant RC2HG005596

  NIH · $1.5M · 2012

• NIH Grant R33CA092752

  NIH · $720k · 2010

• NIH Grant R01HG002918

  NIH · $1.4M · 2008

Frequent coauthors

• Jennifer S Lin

  Kaiser Permanente Center for Health Research

  45 shared

• Ronald N. Zuckermann

  Lawrence Berkeley National Laboratory

  35 shared

• Michelle T. Dohm

  Public Library of Science

  30 shared

• Ann M. Czyzewski

  AbbVie (United States)

  28 shared

• Thomas N. Chiesl

  University of California, Berkeley

  27 shared

• Josefine Eilsø Nielsen

  Roskilde University

  25 shared

• Natalia Molchanova

  Stanford University

  22 shared

• Kent Kirshenbaum

  New York University

  21 shared

Education

• Ph.D., Bioengineering

  Stanford University

  2005

• B.S., Bioengineering

  University of California, San Diego

  2000

Awards & honors

• NIH Pioneer Award (2020)
• Oskar Fischer Award (2022)
• Presidential Early Career Award for Scientists & Engineers (…
• Beckman Young Investigator Award (1999)
• Camille Dreyfus Teacher-Scholar Award (1998)