Cholera is a severe diarrhoeal disease that spreads rapidly and affects millions of people each year, resulting in tens of thousands of deaths. The disease is caused by
Vibrio cholerae
O1 and is characterized by watery diarrhoea that can be lethal if not properly treated. Cholera had not been reported in South America from the late 1800s until 1991, when it was introduced in Peru, wreaking havoc in one of the biggest epidemics reported to date. Within a year, the disease had spread to most of the Latin American region, resulting in millions of cases and thousands of deaths in all affected countries. Despite its aggressive entry, cholera virtually disappeared from the continent after 1999. The progression of the entire epidemic was well documented, making it an ideal model to understand cholera dynamics. In this review, we highlight how the synergy of socioeconomic, political and ecological factors led to the emergence, rapid spread and eventual disappearance of cholera in Latin America. We discuss how measures implemented during the cholera epidemic drastically changed its course and continental dynamics. Finally, we synthesize our findings and highlight potential lessons that can be learned for efficient and standardized cholera management programmes during future outbreaks in non-endemic areas.
Thiopeptide antibiotics are emerging clinical candidates that exhibit potent antibacterial activity against a variety of intracellular pathogens, including Mycobacterium tuberculosis (Mtb). Many thiopeptides directly inhibit bacterial growth by disrupting protein synthesis. However, recent work has shown that one thiopeptide, thiostrepton (TSR), can also induce autophagy in infected macrophages, which has the potential to be exploited for host-directed therapies against intracellular pathogens, such as Mtb. To better define the therapeutic potential of this class of antibiotics, we studied the host-directed effects of a suite of natural thiopeptides that spans five structurally diverse thiopeptide classes, as well as several analogs. We discovered that thiopeptides as a class induce selective autophagic removal of mitochondria, known as mitophagy. This activity is independent of other biological activities, such as proteasome inhibition or antibiotic activity. We also find that many thiopeptides exhibit potent activity against intracellular Mtb in macrophage infection models. However, the thiopeptideinduced mitophagy occurs outside of pathogen-containing autophagosomes and does not appear to contribute to thiopeptide control of intracellular Mtb. These results expand basic understanding of thiopeptide biology and provide key guidance for the development of new thiopeptide antibiotics and host-directed therapeutics.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of death with 1.6 million deaths worldwide reported in 2021. Oral pyrazinamide (PZA) is an integral part of anti-TB regimens, but its prolonged use has the potential to drive development of PZA resistant Mtb. PZA is converted to the active moiety pyrazinoic acid (POA) by the Mtb pyrazinamidase encoded by pncA, and mutations in pncA are associated with the majority of PZA resistance. Conventional oral and parenteral therapies may result in subtherapeutic exposure in the lung, hence direct pulmonary administration of POA may provide an approach to rescue PZA efficacy for treating pncA-mutant PZA-resistant Mtb. The objectives of the current study were to i) develop novel dry powder POA formulations ii) assess their feasibility for pulmonary delivery using physicochemical characterization, iii) evaluate their pharmacokinetics (PK) in the guinea pig model and iv) develop a mechanism based pharmacokinetic model (MBM) using in vivo PK data to select a formulation providing adequate exposure in epithelial lining fluid (ELF) and lung tissue. We developed three POA formulations for pulmonary delivery and characterized their PK in plasma, ELF, and lung tissue following passive inhalation in guinea pigs. Additionally, the PK of POA following oral, intravenous and intratracheal administration was characterized in guinea pigs. The MBM was used to simultaneously model PK data following administration of POA and its formulations via the different routes. The MBM described POA PK well in plasma, ELF and lung tissue. Physicochemical analyses and MBM predictions suggested that POA maltodextrin was the best among the three formulations and an excellent candidate for further development as it has: (i) the highest ELF-to-plasma exposure ratio (203) and lung tissue-to-plasma exposure ratio (30.4) compared with POA maltodextrin and leucine (75.7/16.2) and POA leucine salt (64.2/19.3); (ii) the highest concentration in ELF (𝐶𝑚𝑎𝑥𝐸𝐿𝐹: 171 nM) within 15.5 minutes, correlating with a fast transfer into ELF after pulmonary administration (𝐾𝑃𝑀: 22.6 1/h). The data from the guinea pig allowed scaling, using the MBM to a human dose of POA maltodextrin powder demonstrating the potential feasibility of an inhaled product.
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