The repurposing of Tebipenem pivoxil as alternative therapy for severe gastrointestinal infections caused by extensively drug-resistant Shigella spp.

Background: Diarrhoea remains one of the leading causes of childhood mortality globally. Recent epidemiological studies conducted in low-middle income countries (LMICs) identified Shigella spp. as the first and second most predominant agent of dysentery and moderate diarrhoea, respectively. Antimicrobial therapy is often necessary for Shigella infections; however, we are reaching a crisis point with efficacious antimicrobials. The rapid emergence of resistance against existing antimicrobials in Shigella spp. poses a serious global health problem. Methods: Aiming to identify alternative antimicrobial chemicals with activity against antimicrobial resistant Shigella, we initiated a collaborative academia-industry drug discovery project, applying high-throughput phenotypic screening across broad chemical diversity and followed a lead compound through in vitro and in vivo characterisation. Results: We identified several known antimicrobial compound classes with antibacterial activity against Shigella. These compounds included the oral carbapenem Tebipenem, which was found to be highly potent against broadly susceptible Shigella and contemporary MDR variants for which we perform detailed pre-clinical testing. Additional in vitro screening demonstrated that Tebipenem had activity against a wide range of other non-Shigella enteric bacteria. Cognisant of the risk for the development of resistance against monotherapy, we identified synergistic behaviour of two different drug combinations incorporating Tebipenem. We found the orally bioavailable prodrug (Tebipenem pivoxil) had ideal pharmacokinetic properties for treating enteric pathogens and was effective in clearing the gut of infecting organisms when administered to Shigella-infected mice and gnotobiotic piglets. Conclusions: Our data highlight the emerging antimicrobial resistance crisis and shows that Tebipenem pivoxil (licenced for paediatric respiratory tract infections in Japan) should be accelerated into human trials and could be repurposed as an effective treatment for severe diarrhoea caused by MDR Shigella and other enteric pathogens in LMICs. Funding: Tres Cantos Open Lab Foundation (projects TC239 and TC246), the Bill and Melinda Gates Foundation (grant OPP1172483) and Wellcome (215515/Z/19/Z).

A high throughput screen for next-generation leads targeting malaria parasite transmission.

Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2-1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male-female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population.

Estudio comparativo de la eficacia de los glucocorticoides, mineralocorticoides y vasodilatadores en la recuperación auditiva de pacientes que padecen hipoacusia neurosensorial idiopática de localización coclear. Ensayo clínico preliminar / A comparative study on efficacy of glucocorticoids, mineralocorticoids and vasoactive drugs on reversing hearing loss in patients suffering idiopathic sensorineural cochlear hypoacusis. A preliminary clinical trial

Introducción y objetivos: La hipoacusia neurosensorial (HNS) puede conducir a causar grave deterioro auditivo. Su recuperación funcional parece relacionarse con el control de la homeostasis iónica coclear experimentalmente dependiente de los mineralocorticoides. El objetivo de este trabajo es valorar la eficacia terapéutica comparando 2 modalidades de corticoides frente a los vasodilatadores en pacientes con HNS idopática coclear (HNSIC). Material y métodos: El ensayo dura 3 meses, se realiza en 70 pacientes asignados aleatoriamente en 4 grupos: grupo control, sin medicación, formado por 14 pacientes (8 varones y 6 mujeres); grupo tratado con vasodilatadores formado por 21 pacientes (11 hombres y 10 mujeres); grupo sometido a terapia glucocorticoidea formado por 16 pacientes (10 varones y 6 mujeres); y grupo sometido a terapia mineralocorticoidea formado por 19 pacientes (11 varones y 8 mujeres). La valoración del nivel de pérdida auditiva y su topografía se estiman mediante audiometría tonal liminal (ATL) y potenciales auditivos de tronco cerebral (PEATC). Resultados: Encontramos mejor respuesta al tratamiento con los mineralocorticoides que con los glucocorticoides, siendo la respuesta más pobre para los vasodilatadores. Esta respuesta es mayor en las mujeres que en los hombres, y en general observamos mejor respuesta por parte del oído izquierdo, con independencia del sexo del paciente. Conclusiones: Las ganancias auditivas son significativamente mayores con los mineralocorticoides, seguidas por los glucocorticoides, mientras que con los vasodilatadores las respuestas son pobres y no significativas (AU)

Introduction and objectives: Sensory neural hearing loss (SNHL) is a disorder characterised by an important deterioration of the auditory function. Re-establishing normal ion homeostasis of the endolymph could be related to hearing recovery and it might be mediated by mineralocorticoids. The main purpose of this preliminary, randomized controlled clinical trial was assessing the recovery of idiopathic sensory neural cochlear hearing loss (SNHL) by comparing the efficacy of 2 types of steroids versus vasodilators. Material and methods: The 3-month intervention involved 70 patients, allocated into 4 different groups: a control with no medication, consisting of 14 patients (8 men and 6 women); a vasodilator group of 21 patients (11 men and 10 women); a glucocorticoid group with 16 patients (10 men and 6 women); and a mineralocorticoid therapy group, consisting of 19 patients (11 men and 8 women). The level of hearing loss and its topography were estimated using Liminal Tone Audiometry (LTA) and Auditory Brainstem Response (ABR). Results: Our research found overall greater efficacy of mineralocorticoids versus glucocorticoids and vasodilators. There was better response in women than in men and it was higher from the left ear, regardless of patient gender. Conclusions: The hearing gain was significantly superior in the mineralocorticoid group, followed by the glucocorticoid group. However, the responses to vasodilators were lesser and of low statistical significance (AU)

[A comparative study on efficacy of glucocorticoids, mineralocorticoids and vasoactive drugs on reversing hearing loss in patients suffering idiopathic sensorineural cochlear hypoacusis. A preliminary clinical trial]. / Estudio comparativo de la eficacia de los glucocorticoides, mineralocorticoides y vasodilatadores en la recuperación auditiva de pacientes que padecen hipoacusia neurosensorial idiopática de localización coclear. Ensayo clínico preliminar.

INTRODUCTION AND OBJECTIVES: Sensory neural hearing loss (SNHL) is a disorder characterised by an important deterioration of the auditory function. Re-establishing normal ion homeostasis of the endolymph could be related to hearing recovery and it might be mediated by mineralocorticoids. The main purpose of this preliminary, randomized controlled clinical trial was assessing the recovery of idiopathic sensory neural cochlear hearing loss (SNHL) by comparing the efficacy of 2 types of steroids versus vasodilators. MATERIAL AND METHODS: The 3-month intervention involved 70 patients, allocated into 4 different groups: a control with no medication, consisting of 14 patients (8 men and 6 women); a vasodilator group of 21 patients (11 men and 10 women); a glucocorticoid group with 16 patients (10 men and 6 women); and a mineralocorticoid therapy group, consisting of 19 patients (11 men and 8 women). The level of hearing loss and its topography were estimated using Liminal Tone Audiometry (LTA) and Auditory Brainstem Response (ABR). RESULTS: Our research found overall greater efficacy of mineralocorticoids versus glucocorticoids and vasodilators. There was better response in women than in men and it was higher from the left ear, regardless of patient gender. CONCLUSIONS: The hearing gain was significantly superior in the mineralocorticoid group, followed by the glucocorticoid group. However, the responses to vasodilators were lesser and of low statistical significance.