Target Product Profile and Development Path for Shigellosis Treatment with Antibacterials

Abstract

Enteric infection with Shigella spp. can lead to symptoms ranging from acute watery diarrhea to sudden, severe dysentery. Approximately 212 000 diarrheal deaths annually are attributed to Shigella with a disproportionate impact in low-resource countries. The impact in under-resourced countries was illustrated by a reanalysis of the Global Enteric Multicenter Study which found that Shigella was the leading pathogen associated with moderate-to severe diarrhea in children under 5 years old. While recent studies have highlighted the burden of the disease, there has been a concurrent reduction in therapeutic options for the treatment of shigellosis as drug resistant strains increase in prevalence. In addition, increasing reports of drug resistant shigellosis cases in the men who have sex with men community confirm that the impact is not limited to low-resource countries. Despite the urgent need for new treatments, a target product profile (TPP) has not been established, and there is no clear development path for antibacterial treatments. To address this troubling concern, this manuscript describes a TPP for antishigellosis small molecule therapeutics and a development path that integrates currently available preclinical and clinical models of Shigella infection.

Antibiotic Susceptibility Pattern of Shigella spp. Isolated from Patients Suspected of Acute Gastroenteritis

“…Shigella, a food-borne pathogen, is responsible for acute invasive gastroenteritis and traveler's diarrhea (von Seidlein et al, 2006). It is a major global health problem as it is a prime cause of diarrhea, with 212,000 deaths every year worldwide (Arnold, 2021). It is a major cause of mortality and morbidity in children under the age of five in developing nations (Kotloff et al, 2018).…”

Identification and antibiotic pattern analysis of bacillary dysentery causing bacteria isolated from stool samples of infected patients

“…Bacillary dysentery, like shigellosis, is a leading cause of morbidity and mortality worldwide, particularly in children over five in low- and middle-income nations, including Bangladesh (Arnold 2021 ; Houpt et al 2021 ; Ud-Din and Wahid 2014 ). Annually, bacillary dysentery causes 165 million reported or confirmed cases and 1.1 million fatalities worldwide, primarily in underdeveloped nations (Ali Nor et al 2021 ; Anas et al 2021 ; Duchen et al 2021 ).…”

Development of a Self-Adjuvanting, Cross-Protective, Stable Intranasal Recombinant Vaccine for Shigellosis

“…A vaccine candidate for infectious diseases should be cross-protective to provide protection against heterologous species . Affordability is also a principal factor as shigellosis usually causes more damage in low- and middle-income countries. , Additionally, amenability to mass immunization preferably by circumventing the need for trained personnel (required for vaccine administration) achievable by being noninvasive in nature (for e.g., oral or nasal) can be an advantage. , …”

“…12 Affordability is also a principal factor as shigellosis usually causes more damage in low-and middle-income countries. 22,23 Additionally, amenability to mass immunization preferably by circumventing the need for trained personnel (required for vaccine administration) achievable by being noninvasive in nature (for e.g., oral or nasal) can be an advantage. 12,23 Therefore, the idea of developing a noninvasive, conserved protein-based vaccine against Shigella has received much interest over the past decade.…”

“…22,23 Additionally, amenability to mass immunization preferably by circumventing the need for trained personnel (required for vaccine administration) achievable by being noninvasive in nature (for e.g., oral or nasal) can be an advantage. 12,23 Therefore, the idea of developing a noninvasive, conserved protein-based vaccine against Shigella has received much interest over the past decade. Several proteins that facilitate Shigella invasion into gut epithelium, especially the conserved invasion plasmid antigens (Ipa) of the "type 3 secretion system" (T3SS), have been explored in the recombinant form.…”