Richard Lee
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View article: An open-source screening platform accelerates discovery of drug combinations
An open-source screening platform accelerates discovery of drug combinations Open
Drug combinations are essential to modern medicine, but their discovery remains slow and inefficient as experimental complexity expands rapidly with each additional drug tested. Although modern liquid handling systems enable complex and hi…
View article: Mycobacterium tuberculosis overcomes phosphate starvation by extensively remodelling its lipidome with phosphorus-free lipids
Mycobacterium tuberculosis overcomes phosphate starvation by extensively remodelling its lipidome with phosphorus-free lipids Open
Tuberculosis (TB) is the biggest cause of death from infectious disease worldwide. The causative agent, Mycobacterium tuberculosis (Mtb), possesses a complex cell envelope comprised of multiple classes of unique lipids. The macrophage phag…
View article: Prodrug florfenicol amine is activated by intrinsic resistance to target Mycobacterium abscessus
Prodrug florfenicol amine is activated by intrinsic resistance to target Mycobacterium abscessus Open
Non-tuberculous mycobacteria are emerging pathogens with high intrinsic drug resistance. Among these, Mycobacterium abscessus is particularly refractory owing to its extensive array of resistance mechanisms. Here we introduce florfenicol a…
View article: Development of Pyrimido Pyridazine Analogs through Increased Whole Cell Target Engagement of the Dihydropteroate Synthase Pterin Binding Site in Gram-Negative Bacteria
Development of Pyrimido Pyridazine Analogs through Increased Whole Cell Target Engagement of the Dihydropteroate Synthase Pterin Binding Site in Gram-Negative Bacteria Open
Dihydropteroate synthase (DHPS) is a critical enzyme in the folate biosynthetic pathway of bacteria, fungi, and protozoans. Sulfonamides successfully target the p-aminobenzoic acid (pABA) binding site of DHPS, forming a false product that …
View article: Sterilizing activity of spectinamide MBX-4888A when replacing linezolid in the Nix-TB regimen in the relapsing BALB/c mouse model of tuberculosis
Sterilizing activity of spectinamide MBX-4888A when replacing linezolid in the Nix-TB regimen in the relapsing BALB/c mouse model of tuberculosis Open
Spectinamides have garnered interest as experimental tuberculosis therapeutics owing to their safety profile and efficacy as partner agents when used in conjunction with established regimens in mice. The Nix-TB regimen of bedaquiline, pret…
View article: Characterization of new mouse models of acute and chronic <i>Mycobacterium abscessus</i> infection for antimicrobial drug screening
Characterization of new mouse models of acute and chronic <i>Mycobacterium abscessus</i> infection for antimicrobial drug screening Open
Mycobacterium abscessus (MAB), a rapidly growing non-tuberculous mycobacterium, is becoming increasingly recognized as a significant pathogen affecting humans. These bacteria particularly impact individuals with cystic fibrosis (CF), non-C…
View article: Inhibitors of trehalose-6-phosphate synthase activity in fungal pathogens compromise thermal tolerance pathways
Inhibitors of trehalose-6-phosphate synthase activity in fungal pathogens compromise thermal tolerance pathways Open
Infections caused by fungal pathogens such as Candida and Cryptococcus are associated with high mortality rates, partly due to limitations in the current antifungal arsenal. This highlights the need for antifungal drug targets with novel m…
View article: Sterilizing activity of spectinamide MBX-4888A when replacing linezolid in the Nix- TB regimen in the relapsing BALB/c mouse model of tuberculosis
Sterilizing activity of spectinamide MBX-4888A when replacing linezolid in the Nix- TB regimen in the relapsing BALB/c mouse model of tuberculosis Open
Spectinamides have garnered interest as experimental tuberculosis therapeutics owing to their safety profile and efficacy as partner agents when used in conjunction with established regimens in mice. The Nix-TB regimen of bedaquiline, pret…
View article: Inhibitors of trehalose-6-phosphate synthase activity in fungal pathogens compromise thermal tolerance pathways
Inhibitors of trehalose-6-phosphate synthase activity in fungal pathogens compromise thermal tolerance pathways Open
Infections caused by fungal pathogens such as Candida and Cryptococcus are associated with high mortality rates, partly due to limitations in the current antifungal arsenal. This highlights the need for antifungal drug targets with novel m…
View article: Interstitial Cystitis: a phenotype and rare variant exome sequencing study
Interstitial Cystitis: a phenotype and rare variant exome sequencing study Open
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly understood and underdiagnosed syndrome of chronic bladder/pelvic pain with urinary frequency and urgency. Though IC/BPS can be hereditary, little is known of its genetic etio…
View article: Development of tetracycline analogues with increased aqueous stability for the treatment of mycobacterial infections
Development of tetracycline analogues with increased aqueous stability for the treatment of mycobacterial infections Open
Tetracycline analogs from the minocycline family have recently shown promise for the treatment of non-tuberculous mycobacterial infections. However, current tetracycline and minocycline therapeutics can be limited by tolerability, stabilit…
View article: Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2
Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2 Open
PROTAC® (proteolysis-targeting chimera) molecules induce proximity between an E3 ligase and protein-of-interest (POI) to target the POI for ubiquitin-mediated degradation. Cooperative E3-PROTAC-POI complexes have potential to achieve neo-s…
View article: A modified BPaL regimen for tuberculosis treatment replaces linezolid with inhaled spectinamides
A modified BPaL regimen for tuberculosis treatment replaces linezolid with inhaled spectinamides Open
The Nix-TB clinical trial evaluated a new 6 month regimen containing three oral drugs; bedaquiline (B), pretomanid (Pa), and linezolid (L) (BPaL regimen) for the treatment of tuberculosis (TB). This regimen achieved remarkable results as a…
View article: Neddylation and Its Target Cullin 3 Are Essential for Adipocyte Differentiation
Neddylation and Its Target Cullin 3 Are Essential for Adipocyte Differentiation Open
The ongoing obesity epidemic has raised awareness of the complex physiology of adipose tissue. Abnormal adipocyte differentiation results in the development of systemic metabolic disorders such as insulin resistance and diabetes. The conju…
View article: Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis
Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis Open
The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis . Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profi…
View article: Mycobacterium tuberculosis overcomes phosphate starvation by extensively remodelling its lipidome with phosphorus-free lipids
Mycobacterium tuberculosis overcomes phosphate starvation by extensively remodelling its lipidome with phosphorus-free lipids Open
Tuberculosis (TB) is the biggest cause of death from infectious disease worldwide. The causative agent, Mycobacterium tuberculosis (Mtb), possesses a complex cell envelope that determines many of the key physiologic and virulence propertie…
View article: Author response: A Modified BPaL Regimen for Tuberculosis Treatment replaces Linezolid with Inhaled Spectinamides
Author response: A Modified BPaL Regimen for Tuberculosis Treatment replaces Linezolid with Inhaled Spectinamides Open
The Nix-TB clinical trial evaluated a new 6-month regimen containing three-oral- drugs; bedaquiline (B), pretomanid (Pa) and linezolid (L) (BPaL regimen) for treatment of tuberculosis (TB). This regimen achieved remarkable results as almos…
View article: A Modified BPaL Regimen for Tuberculosis Treatment replaces Linezolid with Inhaled Spectinamides
A Modified BPaL Regimen for Tuberculosis Treatment replaces Linezolid with Inhaled Spectinamides Open
The Nix-TB clinical trial evaluated a new 6-month regimen containing three-oral- drugs; bedaquiline (B), pretomanid (Pa) and linezolid (L) (BPaL regimen) for treatment of tuberculosis (TB). This regimen achieved remarkable results as almos…
View article: Development of Brain Penetrant Pyridazine Pantothenate Kinase Activators
Development of Brain Penetrant Pyridazine Pantothenate Kinase Activators Open
Conversion of pantothenate to phosphopantothenate in humans is the first dedicated step in the coenzyme A (CoA) biosynthesis pathway and is mediated by four isoforms of pantothenate kinase. These enzymes are allosterically regulated by acy…
View article: Sophisticated natural products as antibiotics
Sophisticated natural products as antibiotics Open
In this Review, we explore natural product antibiotics that do more than simply inhibit an active site of an essential enzyme. We review these compounds to provide inspiration for the design of much-needed new antibacterial agents, and exa…
View article: Synthesis and antibacterial action of 3’,6’-disubstituted spectinomycins
Synthesis and antibacterial action of 3’,6’-disubstituted spectinomycins Open
Spectinomycin is an aminocyclitol antibiotic with a unique ribosomal binding site. Prior synthetic modifications of spectinomycin have enhanced potency and antibacterial spectrum through addition at the 6’-position to produce trospectomyci…