Development of 2nd generation aminomethyl spectinomycins that overcome native efflux in Mycobacterium abscessus

Significance The emergence of naturally drug-resistant opportunistic pathogens, such as Mycobacterium abscessus (Mab), presents a growing and deeply concerning public health threat due to few effective therapeutic options and a limited drug development pipeline. This research addresses this critical gap by introducing a unique series of N-ethylene aminomethyl spectinomycin (eAmSPC) analogs that show impressive activity against Mab. We have successfully unraveled the intricate mechanism by which the eAmSPC analogs overcome TetV-mediated efflux, thus reactivating the activity of spectinomycin against Mab. These mechanistic insights are enhanced by extensive developmental endeavors, showcasing the promising potential of this series as treatments against Mab infections.

• Publication year

  2024

• Venue

  Proceedings of the National Academy of Sciences of the United States of America

• Publication date

  2024-01-02

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1073/pnas.2314101120PMID 38165935PMCID 10786304
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Insights into the ribosome function from the structures of non-arrested ribosome–nascent chain complexes

  2022cited by this paper
• Short Synthesis of (+)-Actinobolin: Simple Entry to Complex Small-Molecule Inhibitors of Protein Synthesis.

  2022cited by this paper
• Structural basis for the context-specific action of the classic peptidyl transferase inhibitor chloramphenicol

  2022cited by this paper
• Mab2780c, a TetV-like efflux pump, confers high-level spectinomycin resistance in mycobacterium abscessus.

  2022influential reference
• Insights into the molecular mechanism of translation inhibition by the ribosome-targeting antibiotic thermorubin

  2022cited by this paper
• Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine

  2022cited by this paper
• In vitro activity and in vivo efficacy against non-tuberculous mycobacteria of SPR719, the active moiety of the novel oral benzimidazole prodrug SPR720

  2022cited by this paper
• Structural basis of transcriptional activation by the Mycobacterium tuberculosis intrinsic antibiotic-resistance transcription factor WhiB7.

  2021cited by this paper
• An LC-MS/MS assay and complementary web-based tool to quantify and predict compound accumulation in E. coli

  2021cited by this paper
• Same Game, Different Players: Emerging Pathogens of the CF Lung

  2021cited by this paper
• Synthesis, antibacterial action, and ribosome inhibition of deoxyspectinomycins

  2021cited by this paper
• Translation error clusters induced by aminoglycoside antibiotics

  2021cited by this paper
• Apramycin Overcomes the Inherent Lack of Antimicrobial Bactericidal Activity in Mycobacterium abscessus

  2021cited by this paper
• A synthetic antibiotic class overcoming bacterial multidrug resistance

  2021cited by this paper
• Preclinical Evaluation of Inhalational Spectinamide-1599 Therapy against Tuberculosis.

  2021influential reference
• Sequence Analysis

  2020cited by this paper
• Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance.

  2020cited by this paper
• Rifabutin Is Inactivated by Mycobacterium abscessus Arr

  2020cited by this paper
• Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome

  2020cited by this paper
• Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline: Executive Summary.

  2020cited by this paper
• Efflux Pumps Contribute to Intrinsic Clarithromycin Resistance in Clinical, Mycobacterium abscessus Isolates

  2020cited by this paper
• Non-tuberculous mycobacteria and the rise of Mycobacterium abscessus

  2020cited by this paper
• Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides

  2019cited by this paper
• Incidence and Prevalence of Nontuberculous Mycobacterial Lung Disease in a Large U.S. Managed Care Health Plan, 2008–2015

  2019cited by this paper
• Efficacy of Aminomethyl Spectinomycins against Complex Upper Respiratory Tract Bacterial Infections

  2019cited by this paper
• Structures of Mycobacterium smegmatis 70S ribosomes in complex with HPF, tmRNA, and P-tRNA

  2018cited by this paper
• Antagonism between Front-Line Antibiotics Clarithromycin and Amikacin in the Treatment of Mycobacterium abscessus Infections Is Mediated by the whiB7 Gene

  2017cited by this paper
• Mycobacterium abscessus WhiB7 Regulates a Species-Specific Repertoire of Genes To Confer Extreme Antibiotic Resistance

  2017cited by this paper
• Predictive compound accumulation rules yield a broad-spectrum antibiotic

  2017cited by this paper
• Elucidation of Mycobacterium abscessus aminoglycoside and capreomycin resistance by targeted deletion of three putative resistance genes

  2017cited by this paper
• Structure-Activity Relationships of Spectinamide Antituberculosis Agents: A Dissection of Ribosomal Inhibition and Native Efflux Avoidance Contributions.

  2017cited by this paper
• Antimicrobial susceptibility and MIC distribution of 41 drugs against clinical isolates from China and reference strains of nontuberculous mycobacteria.

  2017cited by this paper
• MultiQC: summarize analysis results for multiple tools and samples in a single report

  2016cited by this paper
• Spectinamides are effective partner agents for the treatment of tuberculosis in multiple mouse infection models

  2016cited by this paper
• Standardized interpretation of antibiotic susceptibility testing and resistance genotyping for Mycobacterium abscessus with regard to subspecies and erm41 sequevar.

  2016cited by this paper
• BRAID: A Unifying Paradigm for the Analysis of Combined Drug Action

  2016cited by this paper
• Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections

  2015cited by this paper
• Mycobacterium abscessus. "Pleased to meet you, hope you guess my name...".

  2015cited by this paper
• Structural insights into the role of rRNA modifications in protein synthesis and ribosome assembly

  2015cited by this paper
• In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics

  2015cited by this paper
• The drug susceptibility profile and inducible resistance to macrolides of Mycobacterium abscessus and Mycobacterium massiliense in Korea.

  2015cited by this paper
• Susceptibility of Mycobacterium abscessus to Antimycobacterial Drugs in Preclinical Models

  2015cited by this paper
• Spectinamides: A New Class of Semisynthetic Anti-Tuberculosis Agents that Overcome Native Drug Efflux

  2014influential reference
• General Platform for Systematic Quantitative Evaluation of Small-Molecule Permeability in Bacteria

  2014cited by this paper
• Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

  2014cited by this paper
• A proton wire to couple aminoacyl-tRNA accommodation and peptide bond formation on the ribosome

  2014cited by this paper
• featureCounts: an efficient general purpose program for assigning sequence reads to genomic features

  2013cited by this paper
• STAR: ultrafast universal RNA-seq aligner

  2013cited by this paper
• TLR13 Recognizes Bacterial 23S rRNA Devoid of Erythromycin Resistance–Forming Modification

  2012cited by this paper
• VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing.

  2012cited by this paper
• Fast gapped-read alignment with Bowtie 2

  2012cited by this paper
• A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff

  2012cited by this paper
• Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7

  2012cited by this paper
• Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration

  2012cited by this paper
• Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria.

  2012cited by this paper
• How Hibernation Factors RMF, HPF, and YfiA Turn Off Protein Synthesis

  2012cited by this paper
• Efflux Pumps of Mycobacterium tuberculosis Play a Significant Role in Antituberculosis Activity of Potential Drug Candidates

  2012cited by this paper
• Synergistic Drug Combinations for Tuberculosis Therapy Identified by a Novel High-Throughput Screen

  2011cited by this paper
• Cutadapt removes adapter sequences from high-throughput sequencing reads

  2011cited by this paper
• Mycobacterium abscessus 肺感染症の臨床的検討

  2010cited by this paper
• A steric block in translation caused by the antibiotic spectinomycin.

  2007cited by this paper
• Structure of the 70S Ribosome Complexed with mRNA and tRNA

  2006cited by this paper
• Ribosomal and non‐ribosomal resistance to oxazolidinones: species‐specific idiosyncrasy of ribosomal alterations

  2002cited by this paper
• Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics

  2000cited by this paper
• Genetic basis for clarithromycin resistance among isolates of Mycobacterium chelonae and Mycobacterium abscessus

  1996cited by this paper
• Pharmacokinetics and fate of 3H-trospectomycin sulphate, a novel aminocyclitol antibiotic, in male and female rats.

  1991influential reference
• Crystal Structure

  year unknowncited by this paper
• equally to this work.

  year unknowninfluential reference

• Mycobacterium abscessus research: learning from challenges

  2026cites this paper
• Macrolide resistance in Mycobacterium abscessus: current insights and future perspectives

  2025cites this paper
• Activity of combinations of bactericidal and bacteriostatic compounds in Mycobacterium abscessus-infected mice: an overview

  2025cites this paper
• Prodrug florfenicol amine is activated by intrinsic resistance to target Mycobacterium abscessus

  2025cites this paper
• How medically important antimicrobials bind to the 30S ribosomal subunit in a bacterial pathogen

  2025cites this paper
• The diversity of clinical Mycobacterium abscessus isolates in morphology, glycopeptidolipids and infection rates in a macrophage model

  2024cites this paper
• Revisiting the potential of natural products in antimycobacterial therapy: advances in drug discovery and semisynthetic solutions.

  2024cites this paper
• Weak links: Advancing target‐based drug discovery by identifying the most vulnerable targets

  2024cites this paper
• Synthesis and antibacterial action of 3’,6’-disubstituted spectinomycins

  2024influential citation
• Toward better cures for Mycobacterium abscessus lung disease

  2024cites this paper
• Development of tetracycline analogues with increased aqueous stability for the treatment of mycobacterial infections.

  2024cites this paper