Targeting the cysteine biosynthesis pathway in microorganisms: Mechanism, structure, and drug discovery.

Owing to the global health crisis of resistant pathogenic infections, researchers are emphasizing the importance of novel prevention and control strategies. Existing antimicrobial drugs predominantly target a few pathways, and their widespread use has pervasively increased drug resistance. Therefore, it is imperative to develop new antimicrobial drugs with novel targets and chemical structures.

Interplay between acetylation and ubiquitination of imitation switch chromatin remodeler Isw1 confers multidrug resistance in .

poses a threat to human health, but anticryptococcal therapy is hampered by the emergence of drug resistance, whose underlying mechanisms remain poorly understood. Herein, we discovered that Isw1, an imitation switch chromatin remodeling ATPase, functions as a master modulator of genes responsible for and multidrug resistance in . Cells with the disrupted gene exhibited profound resistance to multiple antifungal drugs.

Brain glucose induces tolerance of Cryptococcus neoformans to amphotericin B during meningitis.

Antibiotic tolerance is the ability of a susceptible population to survive high doses of cidal drugs and has been shown to compromise therapeutic outcomes in bacterial infections. In comparison, whether fungicide tolerance can be induced by host-derived factors during fungal diseases remains largely unknown. Here, through a systematic evaluation of metabolite-drug-fungal interactions in the leading fungal meningitis pathogen, Cryptococcus neoformans, we found that brain glucose induces fungal tolerance to amphotericin B (AmB) in mouse brain tissue and patient cerebrospinal fluid via the fungal glucose repression activator Mig1.

Fungicide-tolerant persister formation during cryptococcal pulmonary infection.

Bacterial persisters, a subpopulation of genetically susceptible cells that are normally dormant and tolerant to bactericides, have been studied extensively because of their clinical importance. In comparison, much less is known about the determinants underlying fungicide-tolerant fungal persister formation in vivo. Here, we report that during mouse lung infection, Cryptococcus neoformans forms persisters that are highly tolerant to amphotericin B (AmB), the standard of care for treating cryptococcosis.

Novel cytochrome P450s for various hydroxylation of steroids from filamentous fungi.

Hydroxylated steroids are value-added products with diverse biological activities mediated by cytochrome P450 enzymes, however, few has been thoroughly characterized in fungi. This study introduces a rapid identification strategy for filamentous fungi P450 enzymes through transcriptome and bioinformatics analysis. Five novel enzymes (CYP68J5, CYP68L10, CYP68J3, CYP68N1 and CYP68N3) were identified and characterized in Saccharomyces cerevisiae or Aspergillus oryzae.

Genotypic diversity and antifungal susceptibility of Cryptococcus neoformans species complex from China, including the diploid VNIII isolates from HIV-infected patients in Chongqing region.

Although previous studies on the genotypic diversity and antifungal susceptibility of the Cryptococcus neoformans species complex (CNSC) isolates from China revealed ST5 genotype isolates being dominant, the information about the CNSC isolates from Chinese HIV-infected patients is limited. In this study, 171 CNSC isolates from HIV-infected patients in the Chongqing region of Southwest China were genotyped using the International Society for Human and Animal Mycology-multilocus sequence typing consensus scheme, and their antifungal drug susceptibilities were determined following CLSI M27-A3 guidelines. Among 171 isolates, six sequence types (STs) were identified, including the dominant ST5 isolates, the newly reported ST15, and four diploid VNIII isolates (ST632/ST636).

New antifungal strategies: Drug combination and co-delivery.

The growing occurrence of invasive fungal infections and the mounting rates of drug resistance constitute a significant menace to human health. Antifungal drug combinations have garnered substantial interest for their potential to improve therapeutic efficacy, reduce drug doses, reverse, or ameliorate drug resistance. A thorough understanding of the molecular mechanisms underlying antifungal drug resistance and drug combination is key to developing new drug combinations.

Cryptococcus neoformans, a global threat to human health.

Background: Emerging fungal pathogens pose important threats to global public health. The World Health Organization has responded to the rising threat of traditionally neglected fungal infections by developing a Fungal Priority Pathogens List (FPPL). Taking the highest-ranked fungal pathogen in the FPPL, Cryptococcus neoformans, as a paradigm, we review progress made over the past two decades on its global burden, its clinical manifestation and management of cryptococcal infection, and its antifungal resistance.

Regulatory basis for reproductive flexibility in a meningitis-causing fungal pathogen.

Pathogenic fungi of the genus Cryptococcus can undergo two sexual cycles, involving either bisexual diploidization (after fusion of haploid cells of different mating type) or unisexual diploidization (by autodiploidization of a single cell). Here, we construct a gene-deletion library for 111 transcription factor genes in Cryptococcus deneoformans, and explore the roles of these regulatory networks in the two reproductive modes. We show that transcription factors crucial for bisexual syngamy induce the expression of known mating determinants as well as other conserved genes of unknown function.

Functional Characterization of the GlcNAc Catabolic Pathway in Cryptococcus deneoformans.

The amino sugar -acetyl-d-glucosamine (GlcNAc) is the key constituent of cell wall components and plays an important role in pathogenesis in a wide range of fungi. However, catabolism of GlcNAc has not been studied in basidiomycete fungi. In this study, we identified and characterized a gene cluster essential for GlcNAc utilization in Cryptococcus deneoformans, an environmental human fungal pathogen.

Development of Lipo-γ-AA Peptides as Potent Antifungal Agents.

The emergence of drug-resistant fungal pathogens poses great threats to an increasing number of vulnerable populations worldwide, and the need for novel antifungal agents is imperative. In this work, a series of lipo-γ-AA peptides were synthesized and evaluated for their biological activities. One lead, MW, exhibited potent and broad-spectrum antifungal activity.

A Velvet Transcription Factor Specifically Activates Mating through a Novel Mating-Responsive Protein in the Human Fungal Pathogen Cryptococcus deneoformans.

Sexual reproduction facilitates infection by the production of both a lineage advantage and infectious sexual spores in the ubiquitous human fungal pathogen Cryptococcus deneoformans. However, the regulatory determinants specific for initiating mating remain poorly understood. Here, we identified a velvet family regulator, Cva1, that strongly promotes sexual reproduction in C.

Discovery of polypyridyl iridium(III) complexes as potent agents against resistant Candida albicans.

The increasing emergence and spread of drug resistant Candida albicans represent a serious challenge for effective treatment and call for the development of new therapeutic options. To address this need, we synthesized a series of polypyridyl iridium(III) complexes and studied their antimicrobial activities. Herein, one lead iridium(III) complex Ir-3 [(ptpy)Ir(dppz)]PF, with ptpy = 2-(p-tolyl)pyridine and dppz = dipyrido[3,2-a:2',3'-c]phenazine, exhibited potent and broad-spectrum antifungal activities against drug-resistant pathogens and low hemolytic activity toward mammalian cells.

[Biotransformation and enzymatic mechanism of protoberberine alkaloids].

Protoberberine alkaloids belong to the quaternary ammonium isoquinoline alkaloids, and are the main active ingredients in traditional Chinese herbal medicines, like Coptis chinensis. They have been widely used to treat such diseases as gastroenteritis, intestinal infections, and conjunctivitis. Studies have shown that structural modification of the protoberberine alkaloids could produce derivative compounds with new pharmacological effects and biological activities, but the transformation mechanism is not clear yet.

Overcoming the Reticuloendothelial System Barrier to Drug Delivery with a "Don't-Eat-Us" Strategy.

Overcoming the reticuloendothelial system (RES) has long been a vital challenge to nanoparticles as drug carriers. Modification of nanoparticles with polyethylene glycol helps them avoid clearance by macrophages but also suppresses their internalization by target cells. To overcome this paradox, we developed an RES-specific blocking system utilizing a "don't-eat-us" strategy.

Cisplatin protects mice from challenge of by targeting the Prp8 intein.

The Prp8 intein is one of the most widespread eukaryotic inteins, present in important pathogenic fungi, including and species. Because the processed Prp8 carries out essential and non-redundant cellular functions, a Prp8 intein inhibitor is a mechanistically novel antifungal agent. In this report, we demonstrated that cisplatin, an FDA-approved cancer drug, significantly arrested growth of Prp8 intein-containing fungi but only poorly inhibited growth of intein-free species.

Oriented Assembly of Cell-Mimicking Nanoparticles via a Molecular Affinity Strategy for Targeted Drug Delivery.

Cell membrane cloaking is an emerging field in drug delivery in which specific functions of parent cells are conferred to newly formed biomimetic vehicles. A growing variety of delivery systems with diverse surface properties have been utilized for this strategy, but it is unclear whether the affinity of membrane-core pairs could guarantee effective and proper camouflaging. In this study, we propose a concise and effective "molecular affinity" strategy using the intracellular domain of transmembrane receptors as "grippers" during membrane coating.

Recent Advances on Octahedral Polypyridyl Ruthenium(II) Complexes as Antimicrobial Agents.

Recent developments of therapeutic agents based on transition metals have attracted a great deal of attention. Metal drugs have advantages over other small molecule drugs, and it was demonstrated that, in a number of studies, they played an important role in pharmaceutical chemical research and clinical chemotherapy of cancers. It is worthwhile mentioning that octahedral polypyridyl ruthenium(II) complexes have shown remarkable applications in chemical biology and medicinal chemistry over the last decade.

The Discovery of an Iridium(III) Dimer Complex as a Potent Antibacterial Agent against Non-Replicating Mycobacterium smegmatis.

Novel agents are urgently needed to rapidly kill drug-resistant . Noble metal complexes, particularly polypyridyl iridium complexes serving as therapeutic agents, have attracted considerable interest recently, due to their significant cytotoxic or antimicrobial activities. Here, we reported an polypyridyl iridium dimer complex [Ir(ppy)₂Cl]₂ (), with ppy = phenylpyridine, which was found to be active against both exponential growing and non-replicating , with minimum inhibitory concentration values of 2 μg/mL, and exhibited rapid bactericidal kinetics, killing pathogens within 30⁻60 min.

Noncovalent Complexation of Amphotericin B with Poly(β-Amino Ester) Derivates for Treatment of Infection.

Our goal was to improve treatment outcomes for infection by designing nanocarriers that enhance drug-encapsulating capacity and stability. Thus, a noncovalent complex of methoxy poly(ethylene glycol)-poly(lactide)-poly(β-amino ester) (MPEG-PLA-PAE) and amphotericin B (AMB) was developed and characterized. The MPEG-PLA-PAE copolymer was synthesized by a Michael-type addition reaction; the copolymer was then used to prepare the AMB-loaded nanocomplex.