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Vancomycin is a crucial last-resort antibiotic for tackling Gram-positive bacterial infections. However, its potency fails against the more difficult-to-treat Gram-negative bacteria (GNB). Vancomycin derivatives have shown promise as broad-spectrum antibacterials, but are still underexplored. Toward this, we present a novel strategy wherein we substitute the sugar moiety of vancomycin with a dipicolyl amine group, yielding VanNHdipi. This novel glycopeptide enhances its efficacy against vancomycin-resistant bacteria by up to 100-fold. A comprehensive approach involving microbiological assays, biochemical analyses, proteomics, and computational studies unraveled the impact of this design on biological activity. Our investigations reveal that VanNHdipi, like vancomycin, disrupts membrane-bound steps of cell wall synthesis inducing envelope stress, while also interfering with the structural integrity of the cytoplasmic membrane, setting it apart from vancomycin. Most noteworthy is its potency against critical GNB producing metallo-β-lactamases (MBLs). VanNHdipi effectively inactivates various MBLs with IC 50 in the range of 0.2-10 μM resulting in resensitization of MBL-producing bacteria to carbapenems. Molecular docking and molecular dynamics (MD) studies indicate that H-bonding interactions between the sugar moiety of the vancomycin derivative with the amino acids on the surface of NDM-1 facilitate enhanced binding affinity for the enzyme. This work expands the scope of vancomycin derivatives and offers a promising new avenue for combating antibiotic resistance., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Purpose: Worldwide clinical knowledge is expanding rapidly, but physicians have sparse time to review scientific literature. Large language models (eg, Chat Generative Pretrained Transformer [ChatGPT]), might help summarize and prioritize research articles to review. However, large language models sometimes "hallucinate" incorrect information., Methods: We evaluated ChatGPT's ability to summarize 140 peer-reviewed abstracts from 14 journals. Physicians rated the quality, accuracy, and bias of the ChatGPT summaries. We also compared human ratings of relevance to various areas of medicine to ChatGPT relevance ratings., Results: ChatGPT produced summaries that were 70% shorter (mean abstract length of 2,438 characters decreased to 739 characters). Summaries were nevertheless rated as high quality (median score 90, interquartile range [IQR] 87.0-92.5; scale 0-100), high accuracy (median 92.5, IQR 89.0-95.0), and low bias (median 0, IQR 0-7.5). Serious inaccuracies and hallucinations were uncommon. Classification of the relevance of entire journals to various fields of medicine closely mirrored physician classifications (nonlinear standard error of the regression [SER] 8.6 on a scale of 0-100). However, relevance classification for individual articles was much more modest (SER 22.3)., Conclusions: Summaries generated by ChatGPT were 70% shorter than mean abstract length and were characterized by high quality, high accuracy, and low bias. Conversely, ChatGPT had modest ability to classify the relevance of articles to medical specialties. We suggest that ChatGPT can help family physicians accelerate review of the scientific literature and have developed software (pyJournalWatch) to support this application. Life-critical medical decisions should remain based on full, critical, and thoughtful evaluation of the full text of research articles in context with clinical guidelines., (© 2024 Annals of Family Medicine, Inc.)

One carbon (1C) metabolism is critical for cellular viability and physiological homeostasis. Starting from its crucial involvement in purine biosynthesis to posttranslational modification of proteins, 1C metabolism contributes significantly to the development and cellular differentiation through methionine and folate cycles that are pivotal for cellular function. Genetic polymorphisms of several genes of these pathways are implicated in disease pathogenesis and drug metabolism. Metabolic products of 1C metabolism have significant roles in epigenetic modifications through DNA and histone protein methylation. Homocysteine is a product that has clinical significance in the diagnosis and prognosis of several critical illnesses, including chronic immune diseases and cancers. Regulation of the function and differentiation of immune cells, including T-cells, B-cells, macrophages, and so forth, are directly influenced by 1C metabolism and thus have direct implications in several immune disease biology. Recent research on therapeutic approaches is targeting nuclear, cytoplasmic, and mitochondrial 1C metabolism to manage and treat metabolic (i.e., type 2 diabetes), neurodegenerative (i.e., Alzheimer's disease), or immune (i.e., rheumatoid arthritis) diseases. 1C metabolism is being explored for therapeutic intervention as a common determinant for a spectrum of immune and metabolic diseases. Identifying the association or correlation between essential metabolic products of this pathway and disease onset or prognosis would further facilitate the clinical monitoring of diseases., (© 2024 John Wiley & Sons Ltd.)

The problem of antibiotic resistance is on the rise, with multidrug-resistant strains emerging even to the last resort antibiotics. The drug discovery process is often stalled by stringent cut-offs required for effective drug design. In such a scenario, it is prudent to delve into the varying mechanisms of resistance to existing antibiotics and target them to improve antibiotic efficacy. Nonantibiotic compounds called antibiotic adjuvants which target bacterial resistance can be used in combination with obsolete drugs for an improved therapeutic regime. The field of "antibiotic adjuvants" has gained significant traction in recent years where mechanisms other than β-lactamase inhibition have been explored. This review discusses the multitude of acquired and inherent resistance mechanisms employed by bacteria to resist antibiotic action. The major focus of this review is how to target these resistance mechanisms by the use of antibiotic adjuvants. Different types of direct acting and indirect resistance breakers are discussed including enzyme inhibitors, efflux pump inhibitors, inhibitors of teichoic acid synthesis, and other cellular processes. The multifaceted class of membrane-targeting compounds with poly pharmacological effects and the potential of host immune-modulating compounds have also been reviewed. We conclude with providing insights about the existing challenges preventing clinical translation of different classes of adjuvants, especially membrane-perturbing compounds, and a framework about the possible directions which can be pursued to fill this gap. Antibiotic-adjuvant combinatorial therapy indeed has immense potential to be used as an upcoming orthogonal strategy to conventional antibiotic discovery., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Resistance to vancomycin, a life-saving drug against Gram-positive bacterial infections necessitates developing alternative therapeutics. Herein, we report vancomycin derivatives that assimilate mechanisms beyond d-Ala-d-Ala binding. The role of hydrophobicity towards the structure and function of the membrane-active vancomycin showed that alkyl-cationic substitutions favored broad-spectrum activity. The lead molecule, VanQAmC 10 delocalized the cell division protein MinD in Bacillus subtilis , implying an impact on bacterial cell division. Further examination of wild-type, GFP-FtsZ, or GFP-FtsI producing- and Δ amiAC mutants of Escherichia coli revealed filamentous phenotypes and delocalization of the FtsI protein. The findings indicate that VanQAmC 10 also inhibits bacterial cell division, a property previously unknown for glycopeptide antibiotics. The conjunction of multiple mechanisms contributes to its superior efficacy against metabolically active and inactive bacteria, wherein vancomycin is ineffective. Additionally, VanQAmC 10 exhibits high efficacy against methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii in mouse models of infection., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Context: Antibiotics for suspected urinary tract infection (UTI) is appropriate only when an infection is present. Urine culture is definitive but takes >1 day to result. A machine learning urine culture predictor was recently devised for Emergency Department (ED) patients but requires use of urine microscopy ("NeedMicro" predictor), which is not routinely available in primary care (PC). Objective: To adapt this predictor to use only features available in primary care and determine if predictive accuracy generalizes to the primary care setting. We call this the "NoMicro" predictor. Study Design and Analysis: Multicenter, retrospective, observational, cross-sectional analysis. Machine learning predictors were trained using extreme gradient boosting, artificial neural networks, and random forests. Models were trained on the ED dataset and were evaluated on both the ED dataset (internal validation) and the PC dataset (external validation). Setting: United States (US) academic medical centers emergency department and family medicine clinic. Population Studied: 80387 (ED, previously described) and 472 (PC, newly curated) US adults. Instrument: Physicians performed retrospective chart review. The primary outcome extracted was pathogenic urine culture growing ≥100,000 colony forming units. Predictor variables included age; gender; dipstick urinalysis nitrites, leukocytes, clarity, glucose, protein, and blood; dysuria; abdominal pain; and history of UTI. Outcome Measures: Predictor overall discriminative performance (receiver operating characteristic area under the curve, ROC-AUC), performance statistics (e.g., sensitivity, negative predictive value, etc.), and calibration. Results: The "NoMicro" model performs similarly to the "NeedMicro" model in internal validation on the ED dataset: NoMicro ROC-AUC 0.862 (95% CI: 0.856-0.869) vs. NeedMicro 0.877 (95% CI: 0.871-0.884). External validation on the primary care dataset also yielded high performance (NoMicro ROC-AUC 0.850 [95% CI: 0.808-0.889]), despite being trained on Emergency Department data. Simulation of a hypothetical, retrospective clinical trial suggests the NoMicro model could be used to avoid antibiotic overuse by safely withhold antibiotics in low-risk patients. Conclusions: The hypothesis that the NoMicro predictor generalizes to both PC and ED contexts is supported. Prospective trials to determine the real-world impact of using the NoMicro model to reduce antibiotic overuse are appropriate., Competing Interests: None, (© 2023 Annals of Family Medicine, Inc.)

Background: Urinary tract infection (UTI) symptoms are common in primary care, but antibiotics are appropriate only when an infection is present. Urine culture is the reference standard test for infection, but results take >1 day. A machine learning predictor of urine cultures showed high accuracy for an emergency department (ED) population but required urine microscopy features that are not routinely available in primary care (the NeedMicro classifier)., Methods: We redesigned a classifier (NoMicro) that does not depend on urine microscopy and retrospectively validated it internally (ED data set) and externally (on a newly curated primary care [PC] data set) using a multicenter approach including 80,387 (ED) and 472 (PC) adults. We constructed machine learning models using extreme gradient boosting (XGBoost), artificial neural networks, and random forests (RFs). The primary outcome was pathogenic urine culture growing ≥100,000 colony forming units. Predictor variables included age; gender; dipstick urinalysis nitrites, leukocytes, clarity, glucose, protein, and blood; dysuria; abdominal pain; and history of UTI., Results: Removal of microscopy features did not severely compromise performance under internal validation: NoMicro/XGBoost receiver operating characteristic area under the curve (ROC-AUC) 0.86 (95% CI, 0.86-0.87) vs NeedMicro 0.88 (95% CI, 0.87-0.88). Excellent performance in external (PC) validation was also observed: NoMicro/RF ROC-AUC 0.85 (95% CI, 0.81-0.89). Retrospective simulation suggested that NoMicro/RF can be used to safely withhold antibiotics for low-risk patients, thereby avoiding antibiotic overuse., Conclusions: The NoMicro classifier appears appropriate for PC. Prospective trials to adjudicate the balance of benefits and harms of using the NoMicro classifier are appropriate., (© 2023 Annals of Family Medicine, Inc.)

Combination therapy with membrane-targeting compounds is at the forefront because the bacterial membrane is an attractive target considering its role in various multidrug-resistant elements. However, this strategy is crippled by the toxicity associated with these agents. The structural requirements for optimum membrane perturbation and minimum toxicity have not been explored for membrane-targeting antibiotic potentiators or adjuvants. Here, we report the structural influence of different chemical moieties on membrane perturbation, activity, toxicity, and potentiating ability in norspermidine derivatives. It has been shown in this report that weak membrane perturbation, achieved by the incorporation of cyclic hydrophobic moieties, is an effective strategy to design antibiotic adjuvants with negligible in vitro toxicity and activity but good potentiating ability. Aryl or adamantane functionalized derivatives were found to be better resorts as opposed to the acyclic analogues, exhibiting as high as 4096-fold potentiation of multiple classes of antibiotics toward critical Gram-negative superbugs. The mechanism of potentiation was nonspecific, consisting of weak outer-membrane permeabilization, membrane depolarization, and efflux inhibition. This unique concept of "weakly perturbing the membrane" by incorporating cyclic hydrophobic moieties in a chemical design with free amine groups serves as a breakthrough for nontoxic membrane-perturbing adjuvants and has the potential to revitalize the effect of obsolete antibiotics to treat complicated Gram-negative bacterial infections.

Vancomycin, a blockbuster antibiotic of the glycopeptide class, has been a life-saving therapeutic against multidrug-resistant Gram-positive infections. The emergence of glycopeptide resistance has however enunciated the need to develop credible alternatives with potent activity against vancomycin-resistant bacteria. Medicinal chemistry has responded to this challenge through various strategies, one of them being the development of semisynthetic analogues. Many groups, including ours, have been contributing towards the development of semisynthetic vancomycin analogues to tackle vancomycin-resistant bacteria. In this feature article, we have discussed our research contribution to the field of glycopeptides, which includes our strategies and designs of vancomycin analogues incorporating multimodal mechanisms of action. The strategies discussed here, such as conferring membrane activity, enhanced binding to target, multivalency, etc. involve semisynthetic modifications to vancomycin at the carboxy terminal and the amino group of the vancosamine sugar of vancomycin, to develop novel analogues. These analogues have demonstrated their superior efficacy in tackling the inherited forms of vancomycin resistance in Gram-positive and Gram-negative bacteria, including highly drug-resistant strains. More importantly, these analogues also possess the ability to tackle various non-inherited forms of bacterial resistance, such as metabolically dormant stationary-phase and persister cells, bacterial biofilms, and intracellular pathogens. Our derivatives also display superior pharmacokinetics, and less propensity for resistance development, owing to their different modes of action. Through this feature article, we present to the reader a concise picture of the multitude of approaches that can be used to tackle different types of resistance through semisynthetic modifications to vancomycin. We have also highlighted the challenges and lacunae in the field, and potential directions which future research can explore.

Glycopeptides, a class of cell wall biosynthesis inhibitors, have been the antibiotics of choice against drug-resistant Gram-positive bacterial infections. Their unique mechanism of action involving binding to the substrate of cell wall biosynthesis and substantial longevity in clinics makes this class of antibiotics an attractive choice for drug repurposing and reprofiling. However, resistance to glycopeptides has been observed due to alterations in the substrate, cell wall thickening, or both. The emergence of glycopeptide resistance has resulted in the development of synthetic and semisynthetic glycopeptide analogues to target acquired resistance. Recent findings demonstrate that these derivatives, along with some of the FDA approved glycopeptides have been shown to have antimicrobial activity against Gram-negative bacteria, Mycobacteria, and viruses thus expanding their spectrum of activity across the microbial kingdom. Additional mechanisms of action and identification of novel targets have proven to be critical in broadening the spectrum of activity of glycopeptides. This review focuses on the applications of glycopeptides beyond their traditional target group of Gram-positive bacteria. This will aid in making the scientific community aware about the nontraditional activity profiles of glycopeptides, identify the existing loopholes, and further explore this antibiotic class as a potential broad-spectrum antimicrobial agent.

Background: Chronic use of alcohol affects almost every organ system of the body, including male sexual functions. There are only a few Indian studies, which have assessed sexual functions in alcohol-dependent (AD) men and many of them have limitations. This study was aimed to assess sexual functions and marital satisfaction among AD individuals compared to matched controls., Subjects and Methods: A cross-sectional descriptive study was carried out on 70 AD men (study group) and an equal number of matched controls and their spouses in the Department of psychiatry of Jawahar Lal Nehru Medical College, Ajmer. Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised, and Severity of Alcohol Dependence Questionnaire (SADQ) were used to assess withdrawal state and severity of alcohol dependence in the AD group. Marital Adjustment Test (MAT) and Arizona Sexual Experience Scale (ASEX) were used in both study and control groups to assess marital satisfaction and various aspects of sexual functioning., Results: More than half of the men (58.6%) with alcohol dependence were found to have sexual dysfunction compared to only one-fifth in the control group (18.5%). The most commonly affected sexual functions were the ability to get and keep erection (70%) and arousal (62.8%). There was a large negative correlation of MAT scores in the AD group with the SADQ, rho (ρ) = -0.68, and sexual dysfunction (ASEX), rho (ρ) = -0.57. However, the duration of alcohol use did not have any significant association with marital satisfaction., Conclusions: This study showed that participants with AD were more likely to have sexual dysfunction and lower level of marital satisfaction in their spouses. This effect was not because of acute intoxication of alcohol or withdrawal symptoms. We need further research to ascertain whether sexual dysfunction and marital dissatisfaction is a result of alcohol dependence or its reinforcer or both., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Industrial Psychiatry Journal.)

Vancomycin, a natural glycopeptide antibiotic, was used as the antibiotic of last resort for the treatment of multidrug-resistant Gram-positive bacterial infections. However, almost 30 years after its use, resistance to vancomycin was first reported in 1986 in France. This became a major health concern, and alternative treatment strategies were urgently needed. New classes of molecules, including semisynthetic antibacterial compounds and newer generations of the previously used antibiotics, were developed. Semisynthetic derivatives of vancomycin with enhanced binding affinity, membrane disruption ability, and lipid binding properties have exhibited promising results against both Gram-positive and Gram-negative bacteria. Various successful approaches developed to overcome the acquired resistance in Gram-positive bacteria, intrinsic resistance in Gram-negative bacteria, and other forms of noninherited resistance to vancomycin have been discussed in this Perspective.

Context: Both psychiatry as a specialty and mental illnesses carry a lot of stigmatizing attitudes. Even medical professionals are not immune to prevailing stigma. Psychiatrists are perceived to have less scientific attitude, earn less money, to be less respected, and to have less prestige., Aims: The present study was designed to know the attitude of medical students with different years of exposure to medical education, toward psychiatry as a specialty., Settings and Design: The study was conducted at JLN medical College, Ajmer. The participants were divided into two groups, undergraduate and interns, respectively. It was a cross-sectional descriptive study., Materials and Methods: Self-administered sociodemographic and Attitude Toward Psychiatry-30 items questionnaires were given to the second-year and medical intern and the scores were analyzed using appropriate statistical tools., Statistical Analysis Used: Student's t -test and Chi-square test using SPSS version 21., Results: Nearly 84% of second-year medical students and 52% of interns had positive attitude toward psychiatry ( P = 0.001). Only five second-year (5%) and two intern (1.8%) students affirmatively indicated to choose psychiatry as a career choice, while 73% denied choosing psychiatry as a specialty., Conclusions: Second-year medical students showed more positive attitude than the intern group. Increasing negative attitude in higher classes might be due to poor teaching of psychiatry in under graduate training, ridiculous stereotypic comments and remarks by medical teachers and practitioners belonging to other specialty branches., Competing Interests: There are no conflicts of interest.