Genomic and functional insights into antibiotic resistance genes floR and strA linked with the SXT element of Vibrio cholerae non-O1/non-O139.

The emergence and spread of antibiotic-resistant bacterial pathogens are a critical public health concern across the globe. Mobile genetic elements (MGEs) play an important role in the horizontal acquisition of antimicrobial resistance genes (ARGs) in bacteria. In this study, we have decoded the whole genome sequences of multidrug-resistant Vibrio cholerae clinical isolates carrying the ARG-linked SXT, an integrative and conjugative element, in their large chromosomes. As in others, the SXT element has been found integrated into the 5'-end of the prfC gene (which encodes peptide chain release factor 3 involved in translational regulation) on the large chromosome of V. cholerae non-O1/non-O139 strains. Further, we demonstrate the functionality of SXT-linked floR and strAB genes, which confer resistance to chloramphenicol and streptomycin, respectively. The floR gene-encoded protein FloR belongs to the major facilitator superfamily efflux transporter containing 12 transmembrane domains (TMDs). Deletion analysis confirmed that even a single TMD of FloR is critical for the export function of chloramphenicol. The floR gene has two putative promoters, P1 and P2. Sequential deletions reveal that P2 is responsible for the expression of the floR. Deletion analysis of the N- and/or C-terminal coding regions of strA established their importance for conferring resistance against streptomycin. Interestingly, qPCR analysis of the floR and strA genes indicated that both of the genes are constitutively expressed in V. cholerae cells. Further, whole genome-based global phylogeography confirmed the presence of the integrative and conjugative element SXT in non-O1/non-O139 strains despite being non-multidrug resistant by lacking antimicrobial resistance (AMR) gene cassettes, which needs monitoring.

Evaluating Alterations of the Oral Microbiome and Its Link to Oral Cancer among Betel Quid Chewers: Prospecting Reversal through Probiotic Intervention.

Areca nut and slaked lime, with or without tobacco wrapped in Piper betle leaf, prepared as betel quid, is extensively consumed as a masticatory product in many countries across the world. Betel Quid can promote the malignant transformation of oral lesions as well as trigger benign cellular and molecular changes. In the oral cavity, it causes changes at the compositional level in oral microbiota called dysbiosis. This dysbiosis may play an important role in Oral Cancer in betel quid chewers. The abnormal presence and increase of bacteria Fusobacterium nucleatum, Capnocytophaga gingivalis, Prevotella melaninogenica, Peptostreptococcus sp., Porphyromonas gingivalis, and Streptococcus mitis in saliva and/or other oral sites of the cancer patients has attracted frequent attention for its association with oral cancer development. In the present review, the authors have analysed the literature reports to revisit the oncogenic potential of betel quid and oral microbiome alterations, evaluating the potential of oral microbiota both as a driver and biomarker of oral cancer. The authors have also shared a perspective that the restoration of local microbiota can become a potentially therapeutic or prophylactic strategy for the delay or reversal of lip and oral cavity cancers, especially in high-risk population groups.

Glutamate receptor endocytosis and signaling in neurological conditions.

The non-essential amino acid glutamate acts as a major excitatory neurotransmitter and plays a significant role in the central nervous system (CNS). It binds with two different types of receptors, ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs), responsible for the postsynaptic excitation of neurons. They are important for memory, neural development and communication, and learning. Endocytosis and subcellular trafficking of the receptor are essential for the regulation of receptor expression on the cell membrane and excitation of the cells. The endocytosis and trafficking of the receptor are dependent on its type, ligand, agonist, and antagonist present. This chapter discusses the types of glutamate receptors, their subtypes, and the regulation of their internalization and trafficking. The roles of glutamate receptors in neurological diseases are also briefly discussed.

Diarrheal disease and gut microbiome.

Diarrheal disease remains a great public health problem in many countries. Enteric infections caused by several viral, bacterial and parasitic species not only affect the host, but also alter the gut microbiome. The host physiology dictates the intestinal milieu and decides the composition and richness of gut microbiota, which forms a homeostatic ecosystem with numerous functions and provide protection against invading pathogens. During diarrheal infection, patients are affected by gut microbial dysbiosis, which benefits the pathogenic and pro-inflammatory bacteria by enhancing their colonization and proliferation. Gut microbes are associated with several pathophysiological mechanisms, including distorted motility, intestinal barrier dysfunction, malabsorption, immunity disorder, systemic inflammation and changes in the gut-organ axis. Several abiotic factors and childhood malnutrition have negative influences on the gut microbiota, including antibiotics that lead to antibiotic-associated diarrhea and persistent infection. DNA sequencing and bioinformatic analyses enhanced our perception of the gut microbiota, network of metabolic interdependence and their role in health and disease. However, the precise functions of microbiota in gut homeostasis are not well defined. In this chapter, we recapitulate the impact of gut microbiota on diarrheal pathogens, their importance in the immune system and how reshaping the gut microbiota can help during the recovery phase. Additionally, we discuss about impediments and influences beyond diarrhea, particularly on the nutritional status of children.

Region-specific genomic signatures of multidrug-resistant Helicobacter pylori isolated from East and South India.

Helicobacter pylori is a ubiquitous bacterium and contributes significantly to the burden of chronic gastritis, peptic ulcers, and gastric cancer across the world. Adaptive phenotypes and virulence factors in H. pylori are heterogeneous and dynamic. However, limited information is available about the molecular nature of antimicrobial resistance phenotypes and virulence factors of H. pylori strains circulating in India. In the present study, we analyzed the whole genome sequences of 143 H. pylori strains, of which 32 are isolated from two different regions (eastern and southern) of India. Genomic repertoires of individual strains show distinct region-specific signatures. We observed lower resistance phenotypes and genotypes in the East Indian (Kolkata) H. pylori isolates against amoxicillin and furazolidone antibiotics, whereas higher resistance phenotypes to metronidazole and clarithromycin. Also, at molecular level, a greater number of AMR genes were observed in the east Indian H. pylori isolates as compared to the southern Indian isolates. From our findings, we suggest that metronidazole and clarithromycin antibiotics should be used judicially in the eastern India. However, no horizontally acquired antimicrobial resistance gene was observed in the current H. pylori strains. The comparative genome analysis shows that the number of genes involved in virulence, disease and resistance of H. pylori isolated from two different regions of India is significantly different. Single-nucleotide polymorphisms (SNPs) based phylogenetic analysis distinguished H. pylori strains into different clades according to their geographical locations. Conditionally beneficial functions including antibiotic resistance phenotypes that are linked with faster evolution rates in the Indian isolates.

ß-Lactam potentiators to re-sensitize resistant pathogens: Discovery, development, clinical use and the way forward.

ß-lactam antibiotics are one of the most widely used and diverse classes of antimicrobial agents for treating both Gram-negative and Gram-positive bacterial infections. The ß-lactam antibiotics, which include penicillins, cephalosporins, monobactams and carbapenems, exert their antibacterial activity by inhibiting the bacterial cell wall synthesis and have a global positive impact in treating serious bacterial infections. Today, ß-lactam antibiotics are the most frequently prescribed antimicrobial across the globe. However, due to the widespread use and misapplication of ß-lactam antibiotics in fields such as human medicine and animal agriculture, resistance to this superlative drug class has emerged in the majority of clinically important bacterial pathogens. This heightened antibiotic resistance prompted researchers to explore novel strategies to restore the activity of ß-lactam antibiotics, which led to the discovery of ß-lactamase inhibitors (BLIs) and other ß-lactam potentiators. Although there are several successful ß-lactam-ß-lactamase inhibitor combinations in use, the emergence of novel resistance mechanisms and variants of ß-lactamases have put the quest of new ß-lactam potentiators beyond precedence. This review summarizes the success stories of ß-lactamase inhibitors in use, prospective ß-lactam potentiators in various phases of clinical trials and the different strategies used to identify novel ß-lactam potentiators. Furthermore, this review discusses the various challenges in taking these ß-lactam potentiators from bench to bedside and expounds other mechanisms that could be investigated to reduce the global antimicrobial resistance (AMR) burden.

Antimicrobial resistance and virulence in Helicobacter pylori: Genomic insights.

Microbes evolve rapidly by modifying their genome through mutations or acquisition of genetic elements. Antimicrobial resistance in Helicobacter pylori is increasingly prevalent in India. However, limited information is available about the genome of resistant H. pylori isolated from India. Our pan- and core-genome based analyses of 54 Indian H. pylori strains revealed plasticity of its genome. H. pylori is highly heterogenous both in terms of the genomic content and DNA sequence homology of ARGs and virulence factors. We observed that the H. pylori strains are clustered according to their geographical locations. The presence of point mutations in the ARGs and absence of acquired genetic elements linked with ARGs suggest target modifications are the primary mechanism of its antibiotic resistance. The findings of the present study would help in better understanding the emergence of drug-resistant H. pylori and controlling gastric disorders by advancing clinical guidance on selected treatment regimens.

Superior Mesenteric Artery Thrombosis in COVID-19 Pneumonia: an Underestimated Diagnosis-First Case Report in Asia.

The COVID-19 disease caused by novel coronavirus was first reported in Wuhan, China, in December 2019 with 5% patients having severe lung injury. Though this disease primarily presents as a lower respiratory tract infection, multiple digestive manifestations have been reported which are often overlooked. The present case report describes the unusual progression of COVID-19 disease from pneumonia to a procoagulant state leading to superior mesenteric artery thrombosis and subsequent gut ischemia necessitating emergency laparotomy. Coagulopathy in COVID-19 is due to an imbalance in the coagulation homeostasis with increase in prothrombin time, fibrinogen, and D-dimers. Early recognition of abdominal symptoms, diagnosis of pathology, and timely surgical intervention may definitely improve outcome. In the management of any patient with COVID-19 disease, we advocate a comprehensive integrated approach with early recognition of digestive symptoms and their timely intervention which should run parallel to the respiratory management.

Clinical Implications of Vocal Cord-Carina Distance and Tracheal Length in the Indian Population.

OBJECTIVE: Securing the tracheal tube (TT) at a fixed recommended depth of 21/23 cm in female and male patients, respectively, may result in inappropriate placement of the TT in some patients. The aim of the present study was to determine the vocal cord-carina distance (VCD) and tracheal length (TL) to ascertain the optimal depth of TT placement during orotracheal intubation in the adult Indian population. METHODS: A total of 92 adults undergoing elective surgery under general anaesthesia with orotracheal intubation were studied. Surface anatomy airway measurements were noted. A cuffed TT (female size 7 mm ID and male size 8 mm ID) was inserted with the intubation guide mark at level with the vocal cords (VCs). Fiberoptic bronchoscopy-guided measurements were obtained for VCD, TL, TT tip-carina distance, VC-cricoid distance and lip-carina (L-C) distance. RESULTS: The mean±SD VCD was 12.82±2.05 and 12.02±1.44 cm, and TL was 10.14±2.04 and 9.37±1.28 cm in male and female patients, respectively. Statistically significant differences were observed between male and female patients in VCD (p=0.033), TL (p=0.032), L-C distance (p<0.001) and lip-TT tip distance (p<0.001); lip-TT tip distance was 19.50±1.39 cm in male patients and 18.17±1.28 cm in female patients. The L-C distance correlated with patient height, weight and neck length. L-C distance=7.214+0.049×Height+0.320×Neck length+0.033×Weight. CONCLUSION: We recommend placing the TT with its proximal guide mark at the level of VCs in the Indian population. The 21/23 cm rule for tube placement depth in female and male patients, respectively, cannot be routinely followed in the Indian population.