Antibiotic Potentiation as a Promising Strategy to Combat Macrolide Resistance in Bacterial Pathogens.

Antibiotics, which hit the market with astounding impact, were once called miracle drugs, as these were considered the ultimate cure for infectious diseases in the mid-20th century. However, today, nearly all bacteria that afflict humankind have become resistant to these wonder drugs once developed to stop them, imperiling the foundation of modern medicine. During the COVID-19 pandemic, there was a surge in macrolide use to treat secondary infections and this persistent use of macrolide antibiotics has provoked the emergence of macrolide resistance. In view of the current dearth of new antibiotics in the pipeline, it is essential to find an alternative way to combat drug resistance. Antibiotic potentiators or adjuvants are non-antibacterial active molecules that, when combined with antibiotics, increase their activity. Thus, potentiating the existing antibiotics is one of the promising approaches to tackle and minimize the impact of antimicrobial resistance (AMR). Several natural and synthetic compounds have demonstrated effectiveness in potentiating macrolide antibiotics against multidrug-resistant (MDR) pathogens. The present review summarizes the different resistance mechanisms adapted by bacteria to resist macrolides and further emphasizes the major macrolide potentiators identified which could serve to revive the antibiotic and can be used for the reversal of macrolide resistance.

Gut microbiome dysbiosis in malnutrition.

Malnutrition is a global health issue and the leading cause of childhood morbidity and mortality under 5 years old. Malnutrition comprises undernutrition (stunting, wasting, underweight), overweight, and obesity. Infancy and child malnutrition are substantially influenced by a number of variables, such as insufficient nutrients, early birth, intestinal inflammation, and gastrointestinal tract microbiota. A variety of environmental factors have been identified that modulate the structure and diversity of newborns' gut microbiomes and their long-term health. Significant data demonstrate that the functional potency and compositional diversity of the microbiome differ in different types of malnutrition. The divergence in the gut microbiome composition between malnourished and healthy children can be observed at an age as young as 12 months. This focuses on variations in the gut microbiome that may influence adult obesity/health status, beginning in the early years of life. The therapeutic potential of supporting a healthy microbiome in malnourished children is being studied as a technique to aid in the fight against malnutrition. The goal of this chapter was to determine the makeup of gut microbiota in obese and undernourished children under the age of 5 years.

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.

Antibiotic Potentiators Against Multidrug-Resistant Bacteria: Discovery, Development, and Clinical Relevance.

Antimicrobial resistance in clinically important microbes has emerged as an unmet challenge in global health. Extensively drug-resistant bacterial pathogens have cropped up lately defying the action of even the last resort of antibiotics. This has led to a huge burden in the health sectors and increased morbidity and mortality rate across the world. The dwindling antibiotic discovery pipeline and rampant usage of antibiotics has set the alarming bells necessitating immediate actions to combat this looming threat. Various alternatives to discovery of new antibiotics are gaining attention such as reversing the antibiotic resistance and hence reviving the arsenal of antibiotics in hand. Antibiotic resistance reversal is mainly targeted against the antibiotic resistance mechanisms, which potentiates the effective action of the antibiotic. Such compounds are referred to as resistance breakers or antibiotic adjuvants/potentiators that work in conjunction with antibiotics. Many studies have been conducted for the identification of compounds, which decrease the permeability barrier, expression of efflux pumps and the resistance encoding enzymes. Compounds targeting the stability, inheritance and dissemination of the mobile genetic elements linked with the resistance genes are also potential candidates to curb antibiotic resistance. In pursuit of such compounds various natural sources and synthetic compounds have been harnessed. The activities of a considerable number of compounds seem promising and are currently at various phases of clinical trials. This review recapitulates all the studies pertaining to the use of antibiotic potentiators for the reversal of antibiotic resistance and what the future beholds for their usage in clinical settings.

Reactive oxygen mediated apoptosis as a therapeutic approach against opportunistic Candida albicans.

Candida albicans are polymorphic fungal species commonly occurs in a symbiotic association with the host's usual microflora. Certain specific changes in its usual microenvironment can lead to diseases ranging from external mucosal to severally lethal systemic infections like invasive candidiasis hospital-acquired fatal infection caused by different species of Candida. The patient acquired with this infection has a high mortality and morbidity rate, ranging from 40% to 60%. This is an ill-posed problem by its very nature. Hence, early diagnosis and management is a crucial part. Antifungal drug resistance against the first and second generation of antifungal drugs has made it difficult to treat such fatal diseases. After a few dormant years, recently, there has been a rapid turnover of identifying novel drugs with low toxicity to limit the problem of drug resistance. After an initial overview of related work, we examine specific prior work on how a change in oxidative stress can facilitate apoptosis in C. albicans. Subsequently, it was investigated that Candida spp. suppresses the production of ROS mediated host defense system. Here, we have reviewed possibly all the small molecule inhibitors, natural products, antimicrobial peptide, and some naturally derived semi-synthetic compounds which are known to influence oxidative stress, to generate a proper apoptotic response in C. albicans and thus might be a novel therapeutic approach to augment the current treatment options.

Medicinal chemistry updates on quinoline- and endoperoxide-based hybrids with potent antimalarial activity.

The resistance of conventional antimalarial drugs against the malarial parasite continues to pose a challenge to control the disease. The indiscriminate exploitation of the available antimalarials has resulted in increasing treatment failures, which urges on the search for novel lead molecules. Artemisinin-based combination therapy (ACT) is the current WHO-recommended first-line treatment for the majority of malaria cases. Hybrid molecules offer a newer strategy for the development of next-generation antimalarial drugs. These comprise molecules, each with an individual pharmacological activity, linked together into a single hybrid molecule. This approach has been utilized by several research groups to develop molecules with potent antimalarial activity. In this review, we provide an overview of the pivotal roles of quinoline- and endoperoxide-based hybrids as inhibitors of the life-cycle progression of Plasmodium. Based on the exhaustive literature reports, we have collated the structural and functional analyses of quinoline- and endoperoxide-based hybrid molecules that show potency equal to or greater than those of the individual compounds, offering an effective therapeutics option for clinical use.