Drug-resistant tuberculosis (TB), one of the leading causes of death worldwide, arises mainly from spontaneous mutations in the genome of Mycobacterium tuberculosis . There is an urgent need to understand the mechanisms by which the mutations confer resistance in order to identify new drug targets and to design new drugs. Previous studies have reported numerous mutations that confer resistance to anti-TB drugs, but there has been little systematic analysis to understand their genetic background and the potential impacts on the drug target stability and/or interactions. Here, we report the analysis of whole-genome sequence data for 98 clinical M. tuberculosis isolates from a city in southern India. The collection was screened for phenotypic resistance and sequenced to mine the genetic mutations conferring resistance to isoniazid and rifampicin. The most frequent mutation among isoniazid and rifampicin isolates was S315T in katG and S450L in rpoB respectively. The impacts of mutations on protein stability, protein-protein interactions and protein-ligand interactions were analysed using both statistical and machine-learning approaches. Drug-resistant mutations were predicted not only to target active sites in an orthosteric manner, but also to act through allosteric mechanisms arising from distant sites, sometimes at the protein-protein interface.

Highlights d A cryo-EM structure to 2.7 Å resolution of M. tuberculosis KatG with isoniazid d Cryo-EM is able to visualize multiple dynamic binding modes of isoniazid to KatG d Structural disorder in isoniazid resistance mutations is observed d Structural disorder of the resistance mutations results in the lack of heme retention

Hemosuccus pancreaticus is a rare but life-threatening cause of upper gastrointestinal bleeding through the main pancreatic duct. This clinical entity is a difficult diagnosis due to its rarity, intermittent nature of the hemorrhage, and peculiar clinical presentation. It is still considered a surgical problem but advances in medical therapy may enable clinically stable patients to undergo less-invasive angiographic embolization. We chronicle here a unique case of hemosuccus pancreaticus in a patient presenting with melena who could not be diagnosed on multiple standard forward-viewing esophagogastroduodenoscopies and computed tomography angiography. Eventually, side-viewing duodenoscope identified the intermittent bleeding through the ampulla of Vater. This paper illustrates that clinicians should be vigilant for this etiology, especially in patients with intermittent crescendo-decrescendo abdominal pain, acute gastrointestinal hemorrhage, and elevated serum lipase levels. A multidisciplinary team approach with the centralization of gastrointestinal bleed services and a well-established management protocol is of paramount importance to reduce the morbidity and mortality of this disorder. Additionally, this article serves to outline our current understanding of the epidemiology of and risk factors for hemosuccus pancreaticus, the pathophysiology of this disease, and currently available approaches to diagnosis and treatment.

Of the more than 190 distinct species of Mycobacterium genus, many are economically and clinically important pathogens of humans or animals. Among those mycobacteria that infect humans, three species namely Mycobacterium tuberculosis (causative agent of tuberculosis), Mycobacterium leprae (causative agent of leprosy) and Mycobacterium abscessus (causative agent of chronic pulmonary infections) pose concern to global public health. Although antibiotics have been successfully developed to combat each of these, the emergence of drug-resistant strains is an increasing challenge for treatment and drug discovery. Here we describe the impact of the rapid expansion of genome sequencing and genome/pathway annotations that have greatly improved the progress of structure-guided drug discovery. We focus on the applications of comparative genomics, metabolomics, evolutionary bioinformatics and structural proteomics to identify potential drug targets. The opportunities and challenges for the design of drugs for M. tuberculosis, M. leprae and M. abscessus to combat resistance are discussed.

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