Exploring the Recent Pioneering Developments of Small Molecules in Antimalarial Drug Armamentarium: A Chemistry Prospective Appraisal.

Malaria is a very destructive and lethal parasitic disease that causes significant mortality worldwide, resulting in the loss of millions of lives annually. It is an infectious disease transmitted by mosquitoes, which is caused by different species of the parasite protozoan belonging to the genus Plasmodium. The uncontrolled intake of antimalarial drugs often employed in clinical settings has resulted in the emergence of numerous strains of plasmodium that are resistant to these drugs, including multidrug-resistant strains. This resistance significantly diminishes the effectiveness of many primary drugs used in the treatment of malaria. Hence, there is an urgent need for developing unique classes of antimalarial drugs that function with distinct mechanisms of action. In this context, the design and development of hybrid compounds that combine pharmacophoric properties from different lead molecules into a single unit gives a unique perspective towards further development of malaria drugs in the next generation. In recent years, the field of medicinal chemistry has made significant efforts resulting in the discovery and synthesis of numerous small novel compounds that exhibit potent antimalarial properties, while also demonstrating reduced toxicity and desirable efficacy. In light of this, we have reviewed the progress of hybrid antimalarial agents from 2021 up to the present. This manuscript presents a comprehensive overview of the latest advancements in the medicinal chemistry pertaining to small molecules, with a specific focus on their potential as antimalarial agents. As possible antimalarial drugs that might target both the dual stage and multi-stage stages of the parasite life cycle, these small hybrid molecules have been studied. This review explores a variety of physiologically active compounds that have been described in the literature in order to lay a strong foundation for the logical design and eventual identification of antimalarial drugs based on lead frameworks.

Short-chain dehydrogenases in Haemonchus contortus: changes during life cycle and in relation to drug-resistance.

Short-chain dehydrogenases/reductases (SDRs) regulate the activities of many hormones and other signaling molecules and participate in the deactivation of various carbonyl-bearing xenobiotics. Nevertheless, knowledge about these important enzymes in helminths remains limited. The aim of our study was to characterize the SDR superfamily in the parasitic nematode Haemonchus contortus. Genome localization of SDRs was explored, and phylogenetic analysis in comparison with SDRs from free-living nematode Caenorhabditis elegans and the domestic sheep (Ovis aries, a typical host of H. contortus) was constructed. The expression profile of selected SDRs during the life cycle along with differences between the drug-susceptible and drug-resistant strains, were also studied. Genome sequencing enabled the identification of 46 members of the SDR family in H. contortus. A number of genes have no orthologue in the sheep genome. In all developmental stages of H. contortus, SDR1, SDR3, SDR5, SDR6, SDR14, and SDR18 genes were the most expressed, although in individual stages, huge differences in expression levels were observed. A comparison of SDRs expression between the drug-susceptible and drug-resistant strains of H. contortus revealed several SDRs with changed expression in the resistant strain. Specifically, SDR1, SDR12, SDR13, SDR16 are SDR candidates related to drug-resistance, as the expression of these SDRs is consistently increased in most stages of the drug-resistant H. contortus. These findings revealing several SDR enzymes of H. contortus warrant further investigation.

The study of 9,10-dihydroacridine derivatives as a new and effective molecular scaffold for antibacterial agent development.

The emergence of worldwide spreading drug-resistant bacteria has been a serious threat to public health during the past decades. The development of new and effective antibacterial agents to address this critical issue is an urgent action. In the present study, we investigated the antibacterial activity of two 9,10-dihydroacridine derivatives and their mechanism. Both compounds were found possessing strong antibacterial activity against some selected Gram-positive bacteria including MRSA, VISA and VRE. The biological study suggests that the compounds promoted FtsZ polymerization and also disrupted Z-ring formation at the dividing site and consequently, the bacterial cell division is interrupted and causing cell death.

An outbreak of multidrug-resistant Salmonella Kentucky infection in long-nosed fur seals.

An outbreak of salmonellosis occurred in a group of 7 long-nosed fur seals Arctocephalus forsteri undergoing rehabilitation after being found injured and malnourished on beaches along the northern New South Wales and southern Queensland coasts of Australia. Three of the 7 individuals developed clinical disease and died within 3 d. Clinical signs included profuse diarrhea, vomiting, depression, and lethargy. Salmonella enterica subsp. enterica serovar Kentucky (S. Kentucky) was cultured from 2 of the 3 deceased animals. The other 4 animals showed similar signs and recovered following treatment. S. Kentucky (antigenic formula 8,20:i:z6) was isolated from the survivors and tissues recovered from post-mortem samples of deceased animals. The bacterium was susceptible to cephalothin and sulfamethoxazole/trimethoprim and resistant to amoxicillin-clavulanate, ampicillin/amoxicillin, tetracycline, and enrofloxacin. This organism has the potential to cause disease in aquatic wildlife, as well as posing a zoonotic threat to people who utilise the aquatic environment.

Mode of action of antimicrobial agents albofungins in eradicating penicillin- and cephalosporin-resistant Vibrio parahaemolyticus biofilm.

Albofungin is a promising broad-spectrum antimicrobial compound against multidrug-resistant bacteria. In the present study, we further investigated albofungin's biofilm eradication activity and its potential mode of action against drug-resistant Vibrio parahaemolyticus. Among all derivatives, albofungin exhibited the best antibiofilm and antibacterial activity with rapid killing effects at 0.12 µg mL-1. Confocal microscopy observation exhibited that albofungin disrupted V. parahaemolyticus biofilms by killing or dispersing biofilm cells. Meanwhile, scanning electron microscope and fluorescent staining experiments demonstrated that albofungin rapidly destroyed the integrity and permeability of the bacterial cell membrane. Moreover, this study revealed an antibiofilm mechanism of albofungin involving inhibition of peptidoglycan biosynthesis, flagella assembly pathways, and secretion system proteins in V. parahaemolyticus by quantitative proteomics and validation experiments. Our results highlighted albofungin's mechanism of action in planktonic cells and biofilms and suggested further development and potential applications of albofungin for treating infections caused by penicillins-and-cephalosporins-resistant V. parahaemolyticus. IMPORTANCE Infections caused by multidrug-resistant bacteria, as well as a scarcity of new antibiotics, have become a major health threat worldwide. To tackle the demand for new and effective treatments, we investigated the mechanism of action of albofungin, a natural product derived from Streptomyces, which exhibits potent antimicrobial activity against multidrug-resistant bacteria. Albofungin showed potent biofilm eradication activity against penicillins-and-cephalosporins-resistant Vibrio parahaemolyticus, which expresses a novel metallo-ß-lactamase and, thus, reduces their sensitivity to various antibiotics. We observed membrane disruption and permeation mechanisms in planktonic cells and biofilms after albofungin treatment, while albofungin had a weak interaction with bacterial DNA. Moreover, the antibiofilm mechanism of albofungin included inhibition of peptidoglycan biosynthesis, flagellar assembly pathways, and secretion system proteins. Our finding suggested potential applications of albofungin as an antibacterial and antibiofilm therapeutic agent.

In silico Identification of Potential Inhibitors Against Staphylococcus Aureus Tyrosyl-tRNA Synthetase.

BACKGROUND: Drug-resistant Staphylococcus aureus (S. aureus) has spread from nosocomial to community-acquired infections. Novel antimicrobial drugs that are effective against resistant strains should be developed.　S. aureus tyrosyl-tRNA synthetase (saTyrRS) is considered essential for bacterial survival and is an attractive target for drug screening. OBJECTIVE: The purpose of this study was to identify potential new inhibitors of saTyrRS by screening compounds in silico and evaluating them using molecular dynamics (MD) simulations. METHODS: A 3D structural library of 154,118 compounds was screened using the DOCK and GOLD docking simulations and short-time MD simulations. The selected compounds were subjected to MD simulations of a 75-ns time frame using GROMACS. RESULTS: Thirty compounds were selected by hierarchical docking simulations. The binding of these compounds to saTyrRS was assessed by short-time MD simulations. Two compounds with an average value of less than 0.15 nm for the ligand RMSD were ultimately selected. The long-time (75 ns) MD simulation results demonstrated that two novel compounds bound stably to saTyrRS in silico. CONCLUSION: Two novel potential saTyrRS inhibitors with different skeletons were identified by in silico drug screening using MD simulations. The in vitro validation of the inhibitory effect of these compounds on enzyme activity and their antibacterial effect on drug-resistant S. aureus would be useful for developing novel antibiotics.

On a drug-resistant malaria model with susceptible individuals without access to basic amenities.

In this paper, a deterministic malaria transmission model in the presence of a drug-resistant strain is investigated. The model is studied using stability theory of differential equations, optimal control, and computer simulation. The threshold condition for disease-free equilibrium is found to be locally asymptotically stable and can only be achieved in the absence of a drug-resistant strain in the population. The existence of multiple endemic equilibria is also established. Both the Sensitivity Index (SI) of the model parameters and the Incremental Cost-Effectiveness Ratio (ICER) for all possible combinations of the disease-control measures are determined. Our results revealed among others that the most cost-effective strategy for drug-resistant malaria control is the combination of the provision of basic amenities (such as access to clean water, electricity, good roads, health care, and education) and treatment of infective individuals. Therefore, more efforts from policy-makers on the provisions of basic amenities and treatment of infectives would go a long way to combat the malaria epidemic.

New Delhi Metallo-beta-lactamase-producing Enterobacter Cloacae - A Rare Multidrug Resistance Strain in a Caucasian Woman.

New Delhi metallo-beta-lactamase (NDM-1) is a novel metallo-beta-lactamase (MBL) gene carried by some Enterobacteriaceae that induces resistance to most of the antibiotics. First described in a Swedish patient hospitalized in India with an infection due to Klebsiella pneumoniae. NDM-1 makes bacteria resistant to a broad range of beta-lactam antibiotics. These include the antibiotics of the carbapenem family, which are a mainstay for the treatment of antibiotic-resistant bacterial infections. Most of these carbapenem resistant Enterobacteriaceae (CRE) are increasingly recognized in hospital settings and post-acute care settings like long-term acute care settings. Percentage of CRE infections is increasing in the United States of America, and invasive infections with CRE carry high mortality rates and limited treatment options. We here present a rare case of elderly Caucasian woman with CRE cellulitis of both legs with no travel history.

Synthesis and antimycobacterial activity of triterpeni≿ A-ring azepanes.

A series of A-ring azepanones and azepanes derived from betulonic, oleanonic and ursonic acids was synthesized and evaluated for their in vitro antimycobacterial activities against M. tuberculosis (MTB) H37Rv and SDR-TB in the National Institute of Allergy and Infectious Diseases. Triterpenic A-azepano-28-hydroxy-derivatives were synthesized by the reduction with LiAlH4 of triterpenic azepanones available from the Beckmann rearrangement of the corresponding C3-oximes. Modification of azepanes at NH-group and atoms С12, C20, C28 and C29 of triterpenic core led to the derivatives with oxo, epoxy, aminopropyl, oximino and acyl substituents. The primary assay of tested triterpenoids against MTB H37Rv demonstrated their MIC values ranged from 3.125 to >200 µM. Ursane type A-azepano-28-cinnamoates were the most active being 2 and 4 times more efficient than the initial 28-hydroxy-derivative. The follow-up testing revealed A-azepano-28-cinnamoyloxybetulin as a leader compound with MIC 2 and MBC 4 µM against MTB H37Rv and MICs 4, 1 and 1 µM against INH, RIF and OFX resistant strains, respectively. Five oleanane and ursane azepanes pronounced better activity than isoniazid against INH-R1 and rifampicin against INH-R2 strains. This work opens a new direction in the design and synthesis of new antitubercular agents basing on azepanotriterpenoids.

Optimal control of a two-strain tuberculosis-HIV/AIDS co-infection model.

Tuberculosis is a bacterial disease caused by Mycobacterium tuberculosis (TB). The risk for TB infection greatly increases with HIV infection; TB disease occurs in 7-10% of patients with HIV infection each year, increasing the potential for transmission of drug-resistant Mycobacterium tuberculosis strains. In this paper a deterministic model is presented and studied for the transmission of TB-HIV/AIDS co-infection. Optimal control theory is then applied to investigate optimal strategies for controlling the spread of the disease using treatment of infected individuals with TB as the system control variables. Various combination strategies were examined so as to investigate the impact of the controls on the spread of the disease. And incremental cost-effectiveness ratio (ICER) was used to investigate the cost effectiveness of all the control strategies. Our results show that the implementation of the combination strategy involving the prevention of treatment failure in drug-sensitive TB infectious individuals and the treatment of individuals with drug-resistant TB is the most cost-effective control strategy. Similar results were obtained with different objective functionals involving the minimization of the number of individuals with drug-sensitive TB-only and drug-resistant TB-only with the efforts involved in applying the control.

Epidemiology of third-generation cephalosporin-resistant community-acquired Enterobacteria isolated from elderly patients.

AIMS: This survey was made to study the epidemiology of multiresistant bacteria (MRB) in the French community, among elderly patients 65 years of age or more, carrying third-generation cephalosporin-resistant (3GC-resistant) Enterobacteriaceae, and the co-resistance of prescribed antibiotics. METHODS: The data was collected in 2009 in the West of France by MedQual, a network of 174 private laboratories. RESULTS: Two thousand one hundred and sixty strains of the 88,255 identified Enterobacteria strains were 3GC-resistant (2.4%) and 945 of these strains (41.8%) were isolated from elderly patients 65 years of age or more. Escherichia coli was the predominant 3GC-resistant strain (72.7%). 51.4% of the 945 patients in whom a 3GC-resistant strain was isolated produced an extended-spectrum ß-lactamase (ESBL). The main risk factors for infection with the 3GC-resistant strain were hospitalization and antibiotic treatment in the previous year (58.2 and 86.9%, respectively). Hospitalization during the previous year was more frequent among elderly patients who lived at home compared with those who lived in nursing homes (P<0.05). The production of ESBL, among the 945 patients who carried the 3GC-resistant strains, was similar among patients who lived at home compared with those who lived in nursing homes (51.4% versus 49.7%). CONCLUSION: Microbiologists should warn family physicians about MRB isolates with a specific antimicrobial resistance pattern (3GC-resistant, fluoroquinolone-resistant, etc.) to prescribe more effective medications.