Samanthi L. Waidyarachchi

St. Jude Children's Research Hospital

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Richard Lee

St. Jude Children's Research Hospital

Jiuyu Liu

St. Jude Children's Research Hospital

Terry L. Bowlin

Microbiotix (United States)

Michelle M. Butler

Microbiotix (United States)

Bernd Meibohm

University of Tennessee Health Science Center

Erik C. Böttger

University of Zurich

Robin B. Lee

St. Jude Children's Research Hospital

David F. Bruhn

Boehringer Ingelheim (United States)

Anne J. Lenaerts

Colorado State University

Michaël Scherman

Office National d'Études et de Recherches Aérospatiales

Cooperative Institutions

St. Jude Children's Research Hospital

University of Tennessee Health Science Center

National Institutes of Health

Colorado State University

National Institute of Allergy and Infectious Diseases

Microbiotix (United States)

Medicines for Malaria Venture

University of Zurich

Center for Discovery

Rutgers, The State University of New Jersey

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Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Allison Bauman Jansy P. Sarathy Firat Kaya Lisa M. Massoudi Michaël Scherman

Abstract 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 profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. To demonstrate that this translates to more effective cure, we first confirmed the role of rifampin, with or without pyrazinamide, as essential to achieve effective bactericidal responses and sterilizing cure in the current standard of care regimen in chronically infected C3HeB/FeJ mice compared to BALB/c mice. Thus, demonstrating added value in testing clinically relevant regimens in murine models of increasing pathologic complexity. Next we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models including mice exhibiting advanced pulmonary disease can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

Efflux

Spectinomycin

10.1101/2024.05.13.593953

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Citations (1)

Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis

Antimicrobial Agents and Chemotherapy (2024)

Allison Bauman Jansy P. Sarathy Firat Kaya Lisa M. Massoudi Michaël Scherman

ABSTRACT 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 profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

Pyrazinamide

Tolerability

10.1128/aac.00716-24

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Structure–Activity Relationships of Spectinamide Antituberculosis Agents: A Dissection of Ribosomal Inhibition and Native Efflux Avoidance Contributions

ACS Infectious Diseases (2016)

Jiuyu Liu David F. Bruhn Robin B. Lee Zhong Zheng Tanja Janusic

Spectinamides are a novel class of antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Their antitubercular activity is derived from both ribosomal affinity and their ability to overcome intrinsic efflux mediated by the Mycobacterium tuberculosis Rv1258c efflux pump. This study explores the structure-activity relationships through analysis of 50 targeted spectinamides. Compounds are evaluated for ribosomal translational inhibition, MIC activity in Rv1258c efflux pump deficient and wild type tuberculosis strains, and efficacy in an acute model of tuberculosis infection. The results of this study show a narrow structure-activity relationship, consistent with a tight ribosome-binding pocket and strict structural requirements to overcome native efflux. Rationalization of ribosomal inhibition data using molecular dynamics simulations showed stable complex formation for halogenated spectinamides consistent with the long post antibiotic effects observed. The lead spectinamides identified in this study demonstrated potent MIC activity against MDR and XDR tuberculosis and had desirable antitubercular class specific features including low protein binding, low microsomal metabolism, no cytotoxicity, and significant reductions in bacterial burdens in the lungs of mice infected with M. tuberculosis. The structure-activity relationships detailed here emphasize the need to examine efflux-mediated resistance in the design of antituberculosis drugs and demonstrate that it is possible to overcome intrinsic efflux with synthetic modification. The ability to understand the structure requirements for this class has produced a variety of new substituted spectinamides, which may provide useful alternative candidates and promote the further development of this class.

Efflux

Ribosomal protein

10.1021/acsinfecdis.6b00158

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Optimized pyridazinone nutrient channel inhibitors are potent and specific antimalarial leads

Molecular Pharmacology (2022)

Michelle M. Butler Samanthi L. Waidyarachchi Jinfeng Shao Son T. Nguyen Xiaoyuan Ding

Human and animal malaria parasites increase their host erythrocyte permeability to a broad range of solutes as mediated by parasite-associated ion channels. Molecular and pharmacological studies have implicated an essential role in parasite nutrient acquisition, but inhibitors suitable for development of antimalarial drugs are missing. Here, we generated a potent and specific drug lead using Plasmodium falciparum, a virulent human pathogen, and derivatives of MBX-2366, a nanomolar affinity pyridazinone inhibitor from a high-throughput screen. As this screening hit lacks the bioavailability and stability needed for in vivo efficacy, we synthesized 315 derivatives to optimize drug-like properties, establish target specificity, and retain potent activity against the parasite-induced permeability. Using a robust, iterative pipeline, we generated MBX-4055, a derivative active against divergent human parasite strains. MBX-4055 has improved oral absorption with acceptable in vivo tolerability and pharmacokinetics. It also has no activity against a battery of 35 human channels and receptors and is refractory to acquired resistance during extended in vitro selection. Single-molecule and single-cell patch-clamp indicate direct action on the plasmodial surface anion channel, a channel linked to parasite-encoded RhopH proteins. These studies identify pyridazinones as novel and tractable antimalarial scaffolds with a defined mechanism of action.

SIGNIFICANCE STATEMENT

Because antimalarial drugs are prone to evolving resistance in the virulent human P. falciparum pathogen, new therapies are needed. This study has now developed a novel drug-like series of pyridazinones that target an unexploited parasite anion channel on the host cell surface, display excellent in vitro and in vivo ADME properties, are refractory to acquired resistance, and demonstrate a well defined mechanism of action.

Drug Development

10.1124/molpharm.122.000549

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Citations (6)

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

Proceedings of the National Academy of Sciences (2024)

Gregory A. Phelps Martin N. Cheramie Dinesh M. Fernando Petra Selchow Christopher J. Meyer

Mycobacterium abscessus ( Mab ), a nontuberculous mycobacterial (NTM) species, is an emerging pathogen with high intrinsic drug resistance. Current standard-of-care therapy results in poor outcomes, demonstrating the urgent need to develop effective antimycobacterial regimens. Through synthetic modification of spectinomycin (SPC), we have identified a distinct structural subclass of N-ethylene linked aminomethyl SPCs (eAmSPCs) that are up to 64-fold more potent against Mab over the parent SPC. Mechanism of action and crystallography studies demonstrate that the eAmSPCs display a mode of ribosomal inhibition consistent with SPC. However, they exert their increased antimicrobial activity through enhanced accumulation, largely by circumventing efflux mechanisms. The N-ethylene linkage within this series plays a critical role in avoiding TetV-mediated efflux, as lead eAmSPC 2593 displays a mere fourfold susceptibility improvement against Mab Δ tetV, in contrast to the 64-fold increase for SPC. Even a minor shortening of the linkage by a single carbon, akin to 1st generation AmSPC 1950, results in a substantial increase in MICs and a 16-fold rise in susceptibility against Mab Δ tetV . These shifts suggest that longer linkages might modify the kinetics of drug expulsion by TetV, ultimately shifting the equilibrium towards heightened intracellular concentrations and enhanced antimicrobial efficacy. Furthermore, lead eAmSPCs were also shown to synergize with various classes of anti- Mab antibiotics and retain activity against clinical isolates and other mycobacterial strains. Encouraging pharmacokinetic profiles coupled with robust efficacy in Mab murine infection models suggest that eAmSPCs hold the potential to be developed into treatments for Mab and other NTM infections.

Efflux

Mycobacterium abscessus

10.1073/pnas.2314101120

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Citations (7)

Efficacy of Aminomethyl Spectinomycins against Complex Upper Respiratory Tract Bacterial Infections

Antimicrobial Agents and Chemotherapy (2019)

Amy Iverson Christopher J. Meyer Peter Vogel Samanthi L. Waidyarachchi Nisha Das

The most frequent ailment for which antibiotics are prescribed is otitis media (ear infections), which is most commonly caused by

Moraxella (Branhamella) catarrhalis

Acute Otitis Media

Respiratory tract

10.1128/aac.02096-18

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Citations (6)

Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections

Science Translational Medicine (2015)

David F. Bruhn Samanthi L. Waidyarachchi Dora B. Madhura Dimitri Shcherbakov Zhong Zheng

A new series of spectinomycin analogs with potency against drug-resistant bacterial pathogens was designed and developed with a structure-based approach and validated in vitro and in vivo.

Spectinomycin

Respiratory tract

10.1126/scitranslmed.3010572

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Citations (18)

ChemInform Abstract: Synthesis and Biological Activity of Naturally Occurring α‐Glucosidase Inhibitors

ChemInform (2010)

Duncan J. Wardrop Samanthi L. Waidyarachchi

Abstract Review: 176 refs.

10.1002/chin.201102249

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Citations (0)

Synthesis and biological activity of naturally occurring α-glucosidase inhibitors

Natural Product Reports (2010)

Duncan J. Wardrop Samanthi L. Waidyarachchi

Covering: 2005 to the end of 2009

10.1039/b914958a

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Citations (92)

Aminomethyl Spectinomycins as Therapeutics for Drug-Resistant Gonorrhea and Chlamydia Coinfections

Antimicrobial Agents and Chemotherapy (2018)

Michelle M. Butler Samanthi L. Waidyarachchi Kristie L. Connolly Ann E. Jerse Weirui Chai

ABSTRACT Bacterial sexually transmitted infections are widespread and common, with Neisseria gonorrhoeae (gonorrhea) and Chlamydia trachomatis (chlamydia) being the two most frequent causes. If left untreated, both infections can cause pelvic inflammatory disease, infertility, ectopic pregnancy, and other sequelae. The recommended treatment for gonorrhea is ceftriaxone plus azithromycin (to empirically treat chlamydial coinfections). Antibiotic resistance to all existing therapies has developed in gonorrheal infections. The need for new antibiotics is great, but the pipeline for new drugs is alarmingly small. The aminomethyl spectinomycins, a new class of semisynthetic analogs of the antibiotic spectinomycin, were developed on the basis of a computational analysis of the spectinomycin binding site of the bacterial 30S ribosome and structure-guided synthesis. The compounds display particular potency against common respiratory tract pathogens as well as the sexually transmitted pathogens that cause gonorrhea and chlamydia. Here, we demonstrate the in vitro potencies of several compounds of this class against both bacterial species; the compounds displayed increased potencies against N. gonorrhoeae compared to that of spectinomycin and, significantly, demonstrated activity against C. trachomatis that is not observed with spectinomycin. Efficacies of the compounds were compared to those of spectinomycin and gentamicin in a murine model of infection caused by ceftriaxone/azithromycin-resistant N. gonorrhoeae ; the aminomethyl spectinomycins significantly reduced the colonization load and were as potent as the comparator compounds. In summary, data produced by this study support aminomethyl spectinomycins as a promising replacement for spectinomycin and antibiotics such as ceftriaxone for treating drug-resistant gonorrhea, with the added benefit of treating chlamydial coinfections.

Spectinomycin

Neisseria gonorrhoeae

Pelvic inflammatory disease

10.1128/aac.00325-18

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Citations (28)