Biology subjects

Cummings, J. E.

Publications and source records attributed to Cummings, J. E..

4 recordsLinked to original sources

bioRxiv2025

Pharmacokinetics and In vivo Efficacy of Epetraborole against Burkholderia pseudomallei

Melioidosis, caused by Burkholderia pseudomallei, remains a major therapeutic challenge due to high relapse rates and intrinsic antibiotic resistance. Epetraborole (EBO), a leucyl-tRNA synthetase inhibitor, represents a novel therapeutic approach with a distinct mechanism of action compared to standard-of-care antibiotics. Preclinical studies included MIC determination, pharmacokinetic (PK) profiling, dose range and fractionation studies, and efficacy assessments in a 24-hour post-bacterial challenge model of a murine B. pseudomallei lung infection. EBO demonstrated a clear dose-dependent reduction in lung bacterial burden. Doses [≥]200 mg/kg (achieving AUC-2 [~]110 {micro}g{middle dot}h/mL) produced >1.6 log CFU decreases from the start-of-therapy baseline across all ten B. pseudomallei strains. Notably, an AUC-2 of [~]110 {micro}g{middle dot}h/mL was achieved in humans with a 2000 mg IV dose in a phase 1 clincial trial where doses up to 4000 mg per day for 14 days were well tolerated with no serious adverse events or dose-limiting adverse events. When EBO doses of 600, 300 and 100 mg/kg SC were fractionated by once, twice and three times a day against the B. pseudomallei strain NCTC7383, which represents the MIC100 strain, the efficacy indicated that the pharmacokinetics-pharmacodynamics (PK/PD) driver of epetraborole is total drug exposure (AUC) rather than peak concentration (Cmax) or time above MIC. The inhibition of leucyl-tRNA synthetase represents a unique molecular target, reducing cross-resistance potential with existing {beta}-lactam antibiotics and enabling combination therapy strategies. These findings substantiate EBO as a promising therapeutic option for clinical melioidosis to improve treatment outcomes. Notably, this study represents the first demonstration of in vivo efficacy against a panel of ten genetically and geographically diverse B. pseudomallei strains in a murine model. This unprecedented breadth of strain coverage provides strong evidence of EBOs robust and strain-independent therapeutic potential. Author SummaryMelioidosis is a life-threatening disease caused by Burkholderia pseudomallei, a bacterium found in soil and water in tropical regions. It is challenging to treat because it is often resistant to standard antibiotics, requires long courses of therapy, and can relapse even after treatment. New treatment options are urgently needed. Epetraborole is an experimental antibiotic with a novel mechanism that blocks bacterial protein synthesis. In this study, we tested how well epetraborole works in mice infected with B. pseudomallei, using ten different strains of the bacteria collected from geographically diverse regions. This is the first study to test a melioidosis treatment against such a broad panel of B. pseudomallei strains in an animal model. We found that epetraborole significantly reduced bacterial counts in the lungs of infected mice. The antibiotic remained effective even against strains with higher resistance and high bacterial loads 24 hours after infection, showing promise for severe clinical infections. Our findings suggest that epetraborole could be a valuable addition to existing melioidosis treatments, especially in regions with limited therapeutic options.

microbiology↗

bioRxiv2023

Rapid in vitro activity of telavancin against Bacillus anthracis and in vivo protection against inhalation anthrax infection in the rabbit model

Anthrax, caused by the bacterium Bacillus anthracis, is a zoonotic disease that manifests in various forms in human infection, depending on the route of infection. Inhalation anthrax, the most detrimental form of the disease, comes about from the inhalation of anthrax spores and progresses to severe life-threatening conditions late in infection. Notably, there are FDA-approved antibiotics that are effective at treating the disease when administered promptly; however, these antibiotics would be rendered useless against strains of B. anthracis that were genetically modified to be resistant to these antibiotics. Consequently, the search for new and effective therapeutics to combat anthrax infection continues. In this study, telavancin (Vibativ(R)), a semisynthetic lipoglycopeptide antibiotic, was assessed for in vitro activity against 17 B. anthracis strains and tested for the protective efficacy against inhalation anthrax infection in the rabbit model. Telavancin demonstrated potent in vitro activity against B. anthracis which led us to test its efficacy in the rabbit inhalation anthrax model. Rabbits were infected with a lethal dose of anthrax spores via the inhalation route and treated intravenously with telavancin at 30 mg/kg every 12 hours, a dose that mimics the levels measured in the serum of humans, for 5 days upon detection of antigenemia. Blood samples were collected at various times post-infection to assess the level of bacteremia and antibody production, and tissues were collected to determine bacterial load. The animals body temperatures were also recorded. Telavancin conveyed 100% survival in this model. Moreover, the dosage of telavancin used for the study effectively cleared B. anthracis from the bloodstream and organ tissues, even more effectively than a humanized dose of levofloxacin. Collectively, the low MICs against all strains tested and rapid bactericidal in vivo activity demonstrate that telavancin has the potential to be an effective alternative for the treatment or prophylaxis of anthrax infection. Author SummaryBacillus anthracis, the causative agent of anthrax, continues to interest the research community due to its past and future potential use as bioweapon. Importantly, as a bacterial pathogen, B. anthracis is capable of developing resistance to the antibiotics currently used to treat the infection, either naturally or by deliberate, nefarious means. Consequently, there remains a need to discover, develop, and/or repurpose new antibiotics that would be effective at treating anthrax infection. In this study, we evaluated the antibacterial activity of telavancin, a semisynthetic glycopeptide antibiotic clinically approved to treat complicated skin and skin structure infections, against various strains of B. anthracis in vitro, and we assessed the protective efficacy of telavancin against inhalation anthrax infection in the rabbit model. We show that telavancin is very potent against numerous B. anthracis strains in vitro, and its level of potency surpassed that of another antibiotic currently approved and used to prevent anthrax infection. Moreover, we show that telavancin protects against inhalation anthrax infection in vivo. Overall, our findings support the use of telavancin as an effective therapeutic for anthrax infection.

microbiology↗

bioRxiv2021

TPR1, a novel rifampin derivative demonstrates efficacy alone and in combination with doxycycline against the NIAID Category A Priority Pathogen F. tularensis

ObjectivesFrancisella tularensis is a highly virulent and contagious gram-negative intracellular bacterium that causes the disease tularemia in mammals and is classified as a Category A priority pathogen. The high infectivity, difficulty of obtaining a durable cure of disseminated disease and the emergence of drug resistance warrants investigation of new drugs that can be used alone and in combination with existing standard of care clinical drugs. MethodsWe utilized a systematic analysis of antibacterial potency, extent of dissemination by analysis of bacterial burden in a secondary vital organ, and survival rates to assess the efficacy of a novel rifampicin derivative, TPR1. The efficacy of TPR1 was evaluated alone and in combination with the standard of care drug, doxycycline, against Type A F. tularensis Schu S4 using a lethal pulmonary model of infection in mice. ResultsTPR1 has an MIC value range of 0.125-4 mg/L against reference laboratory strain SchuS4 and a panel of clinical strains. TPR1 alone reduced the bacterial burden in the lungs and spleen at 40 mg/kg and 80 mg/kg, and no antagonism was observed when co-administered with doxycycline. Dosing at 40 mg/kg doxycycline reduced the bacterial burden by 1 Log10 CFU in the lungs and 4 Log10 CFU spleen in comparison to untreated controls. Co-administration of TPR1 and doxycycline demonstrated efficacy upon treatment withdrawal after 4 days of treatment, and 100% survival. ConclusionsSignificantly, TPR1 demonstrated efficacy when delivered alone and in combination with doxycycline, which provides compelling evidence of a superior treatment strategy that would normally rely on a single chemotherapeutic for efficacy. In addition, this work substantiates the use of rifampicin derivatives as a platform for the development of novel treatments to other bacterial agents in addition to tularemia.

microbiology↗

bioRxiv2020

Profiling susceptibility of NIAID Category A and B priority and emerging pathogens to define strain panels for drug discovery and active drug classes

Drug susceptibility profiles of NIAID Category A and B priority and emerging pathogens to standard of care drugs were assessed to determine susceptibility against clinical strains in addition to reference laboratory strains to establish a comparison resource for the performance of drug candidates, to define non-redundant minimal strain panels for individual species and the group of species for use in drug screening programs, and provide pharmacophore classification. Profiling of standard of care drugs against strains of each species revealed a broad spectrum of susceptibility among strains in each species with important differences between standard laboratory reference strains and strains sof clinical origin. Unbiased hierarchical clustering analyses of strain susceptibilities within each species group and strains from all the species identified subsets of non-redundant strains that are able to classify the susceptibility range for each species and able to classify all the species. This analysis established a reduced targeted set of Category A and B priority pathogen strains for testing the potency of drug candidates against each species and pan-species. This approach also discriminated pharmacophore classification for each species. This information can be applied to directed screening efforts to guide the selection of drug classes for derivatization and repurposing, and advance drug candidates with the greatest potential for efficacy against NIAID Category A and B priority and emerging pathogens.

microbiology↗