Innovative Strategies in Drug Repurposing to Tackle Intracellular Bacterial Pathogens.

Intracellular bacterial pathogens pose significant public health challenges due to their ability to evade immune defenses and conventional antibiotics. Drug repurposing has recently been explored as a strategy to discover new therapeutic uses for established drugs to combat these infections. Utilizing high-throughput screening, bioinformatics, and systems biology, several existing drugs have been identified with potential efficacy against intracellular bacteria.

Resistance is futile: targeting multidrug-resistant bacteria with Cys-rich cyclic polypeptides.

The search for novel antimicrobial agents to combat microbial pathogens is intensifying in response to rapid drug resistance development to current antibiotic therapeutics. The use of disulfide-rich head-to-tail cyclized polypeptides as molecular frameworks for designing a new type of peptide antibiotics is gaining increasing attention among the scientific community and the pharmaceutical industry. The use of macrocyclic peptides, further constrained by the presence of several disulfide bonds, makes these peptide frameworks remarkably more stable to thermal, biological, and chemical degradation showing better activities when compared to their linear analogs.

Understanding microRNAs in the Context of Infection to Find New Treatments against Human Bacterial Pathogens.

The development of RNA-based anti-infectives has gained interest with the successful application of mRNA-based vaccines. Small RNAs are molecules of RNA of <200 nucleotides in length that may control the expression of specific genes. Small RNAs include small interference RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), or microRNAs (miRNAs).

Novel Methods to Identify Oxidative Stress-Producing Antibiotics.

Antibiotherapy is the main therapeutic strategy in the fight against bacterial pathogens. However, the misuse of antimicrobials has led to the appearance of antimicrobial-resistant strains. The rate at which we isolate multidrug-resistant bacteria is now much faster than the discovery rate of new antimicrobials.

Alternative Anti-Infective Treatments to Traditional Antibiotherapy against Staphylococcal Veterinary Pathogens.

The genus encompasses many species that may be pathogenic to both humans and farm animals. These bacteria have the potential to acquire multiple resistant traits to the antimicrobials currently used in the veterinary or medical settings. These pathogens may commonly cause zoonoses, and the infections they cause are becoming difficult to treat due to antimicrobial resistance.

Novel Treatments against Based on Drug Repurposing.

Tuberculosis is the leading cause of death, worldwide, due to a bacterial pathogen. This respiratory disease is caused by the intracellular pathogen and produces 1.5 million deaths every year.

Oxidative Stress-Generating Antimicrobials, a Novel Strategy to Overcome Antibacterial Resistance.

Antimicrobial resistance is becoming one of the most important human health issues. Accordingly, the research focused on finding new antibiotherapeutic strategies is again becoming a priority for governments and major funding bodies. The development of treatments based on the generation of oxidative stress with the aim to disrupt the redox defenses of bacterial pathogens is an important strategy that has gained interest in recent years.

A Novel Screening Strategy Reveals ROS-Generating Antimicrobials That Act Synergistically against the Intracellular Veterinary Pathogen .

is a facultative intracellular pathogen that causes infections in foals and many other animals such as pigs, cattle, sheep, and goats. Antibiotic resistance is rapidly rising in horse farms, which makes ineffective current antibiotic treatments based on a combination of macrolides and rifampicin. Therefore, new therapeutic strategies are urgently needed to treat infections caused by antimicrobial resistant strains.

Methionine sulfoxide reductase B from catalyzes sulfoxide reduction via an intramolecular disulfide cascade.

is a human pathogen that causes diphtheria. In response to immune system-induced oxidative stress, expresses antioxidant enzymes, among which are methionine sulfoxide reductase (Msr) enzymes, which are critical for bacterial survival in the face of oxidative stress. Although some aspects of the catalytic mechanism of the Msr enzymes have been reported, several details still await full elucidation.

Mycoredoxins Are Required for Redox Homeostasis and Intracellular Survival in the Actinobacterial Pathogen .

is a facultative intracellular pathogen that can survive within macrophages of a wide variety of hosts, including immunosuppressed humans. Current antibiotherapy is often ineffective, and novel therapeutic strategies are urgently needed to tackle infections caused by this pathogen. In this study, we identified three mycoredoxin-encoding genes () in the genome of , and we investigated their role in virulence.

Structural snapshots of OxyR reveal the peroxidatic mechanism of HO sensing.

Hydrogen peroxide (HO) is a strong oxidant capable of oxidizing cysteinyl thiolates, yet only a few cysteine-containing proteins have exceptional reactivity toward HO One such example is the prokaryotic transcription factor OxyR, which controls the antioxidant response in bacteria, and which specifically and rapidly reduces HO In this study, we present crystallographic evidence for the HO-sensing mechanism and HO-dependent structural transition of OxyR by capturing the reduced and HO-bound structures of a serine mutant of the peroxidatic cysteine, and the full-length crystal structure of disulfide-bonded oxidized OxyR. In the HO-bound structure, we pinpoint the key residues for the peroxidatic reduction of HO, and relate this to mutational assays showing that the conserved active-site residues T107 and R278 are critical for effective HO reduction. Furthermore, we propose an allosteric mode of structural change, whereby a localized conformational change arising from HO-induced intramolecular disulfide formation drives a structural shift at the dimerization interface of OxyR, leading to overall changes in quaternary structure and an altered DNA-binding topology and affinity at the catalase promoter region.

Microbial Production of Ethanol From Sludge Derived From an Urban Wastewater Treatment Plant.

A collection of lipase-producing microorganisms was isolated from sludge derived from an urban wastewater treatment plant. The microorganisms with the highest levels of lipase activity were selected in order to use triglycerides present in the sludge effectively and were then transformed with genes for the production of ethanol. The transgenic strains showed high growth rates in diluted sludge and produced lipase protein in order to utilize fat present in the sludge, which provides an abundant source of carbon.

The Arsenic Detoxification System in Corynebacteria: Basis and Application for Bioremediation and Redox Control.

Arsenic (As) is widespread in the environment and highly toxic. It has been released by volcanic and anthropogenic activities and causes serious health problems worldwide. To survive arsenic-rich environments, soil and saprophytic microorganisms have developed molecular detoxification mechanisms to survive arsenic-rich environments, mainly by the enzymatic conversion of inorganic arsenate (As) to arsenite (As) by arsenate reductases, which is then extruded by arsenite permeases.