Trachymyrmex septentrionalis ants promote fungus garden hygiene using Trichoderma-derived metabolite cues.

Fungus-growing ants depend on a fungal mutualist that can fall prey to fungal pathogens. This mutualist is cultivated by these ants in structures called fungus gardens. Ants exhibit weeding behaviors that keep their fungus gardens healthy by physically removing compromised pieces. However, how ants detect diseases of their fungus gardens is unknown. Here, we applied the logic of Koch's postulates using environmental fungal community gene sequencing, fungal isolation, and laboratory infection experiments to establish that Trichoderma spp. can act as previously unrecognized pathogens of Trachymyrmex septentrionalis fungus gardens. Our environmental data showed that Trichoderma are the most abundant noncultivar fungi in wild T. septentrionalis fungus gardens. We further determined that metabolites produced by Trichoderma induce an ant weeding response that mirrors their response to live Trichoderma. Combining ant behavioral experiments with bioactivity-guided fractionation and statistical prioritization of metabolites in Trichoderma extracts demonstrated that T. septentrionalis ants weed in response to peptaibols, a specific class of secondary metabolites known to be produced by Trichoderma fungi. Similar assays conducted using purified peptaibols, including the two previously undescribed peptaibols trichokindins VIII and IX, suggested that weeding is likely induced by peptaibols as a class rather than by a single peptaibol metabolite. In addition to their presence in laboratory experiments, we detected peptaibols in wild fungus gardens. Our combination of environmental data and laboratory infection experiments strongly support that peptaibols act as chemical cues of Trichoderma pathogenesis in T. septentrionalis fungus gardens.

Synthesis, antibiofilm activity and molecular docking of N-acylhomoserine lactones containing cinammic moieties.

We prepared a series of cinnamoyl-containing furanones by an affordable and short synthesis. The nineteen compounds hold a variety of substituents including electron-donating, electron-withdrawing, bulky and meta-substituted phenyls, as well as heterocyclic rings. Compounds showed antibiofilm activity in S. aureus, K. pneumoniae and, more pronounced, against P. aeruginosa. The disruption of quorum sensing (QS) was tested using the violacein test and molecular docking predicted the antagonism of LasR as a plausible mechanism of action. The trimethoxylated and diene derivatives showed the best antibiofilm and anti-QS properties, thus becoming candidates for further modifications.

Integrating Taxonomic and Chemical Diversity of Mangrove-Associated Ascomycetes to Discover or Repurpose Bioactive Natural Products.

Natural product reisolation is a bottleneck when discovering new bioactive chemical entities from nature. To overcome this issue, multi-informative approaches integrating several layers of data have been applied with promising results. In this study, integration of taxonomy, nontargeted metabolomics, and bioactivity information resulted in the selection of Scytalidium sp. IQ-074 and Diaporthe sp. IQ-053 to isolate new natural products active against hPTP1B1-400 and repurpose others as antibiotics. Strain IQ-074 was selected based on the hypothesis that investigating poorly studied and highly metabolic taxa could lead to the isolation of new chemical entities. A chemical investigation of IQ-074 resulted in the isolation of papyracillic acid A (14), 7-deoxypapyracillic acid A (15a and 15b), and linear polyketides scytalpolyols A-D (16-19). Compound 17 inhibited hPTP1B1-400 with a half-maximal inhibitory concentration of 27.0 ± 1.7 µM. Diaporthe sp. IQ-053 was selected based on its antibacterial properties against pathogenic strains. Its chemical investigation yielded dothiorelones A (20) and I (21), cytosporones B (22) and C (23), pestalotiopsone B (24), and diaporthalasin (25). Compounds 22 and 25 inhibited the growth of Staphylococcus aureus and Staphylococcus epidermidis 42R and moderately inhibited the growth of Acinetobacter baumannii A564, a pandrug-resistant bacterium.

Biological Dark Matter Exploration using Data Mining for the Discovery of Antimicrobial Natural Products.

The discovery of novel antimicrobials has significantly slowed down over the last three decades. At the same time, humans rely increasingly on antimicrobials because of the progressive antimicrobial resistance in medical practices, human communities, and the environment. Data mining is currently considered a promising option in the discovery of new antibiotics. Some of the advantages of data mining are the ability to predict chemical structures from sequence data, anticipation of the presence of novel metabolites, the understanding of gene evolution, and the corroboration of data from multiple omics technologies. This review analyzes the state-of-the-art for data mining in the fields of bacteria, fungi, and plant genomic data, as well as metabologenomics. It also summarizes some of the most recent research accomplishments in the field, all pinpointing to innovation through uncovering and implementing the next generation of antimicrobials.

Absolute configuration and protein tyrosine phosphatase 1B inhibitory activity of xanthoepocin, a dimeric naphtopyrone from Penicillium sp. IQ-429.

Protein tyrosine phosphatase 1B (PTP1B) is an active target for developing drugs to treat type II diabetes, obesity, and cancer. However, in the past, research programs targeting this enzyme focused on discovering inhibitors of truncated models (hPTP1B1-282, hPTP1B1-298, or hPTP1B1-321), losing valuable information about the ligands' mechanism of inhibition and selectivity. Nevertheless, finding an allosteric site in hPTP1B1-321, and the full-length (hPTP1B1-400) protein expression, have shifted the strategies to discover new PTP1B inhibitors. Accordingly, as part of a research program directed at finding non-competitive inhibitors of hPTP1B1-400 from Pezizomycotina, the extract of Penicillium sp. (IQ-429) was chemically investigated. This study led to xanthoepocin (1) isolation, which was elucidated by means of spectroscopic and spectrometric data. The absolute configuration of 1 was determined to be 7R8S9R7'R8'S9'R by comparing the theoretical and experimental ECD spectra and by GIAO-NMR DP4 + statistical analysis. Xanthoepocin (1) inhibited the phosphatase activity of hPTP1B1-400 (IC50 value of 8.8 ± 1.0 µM) in a mixed type fashion, with ki and αki values of 5.5  and 6.6 µM, respectively. Docking xanthoepocin (1) with a homologated model of hPTP1B1-400 indicated that it binds in a pocket different from the catalytic triad at the interface of the N and C-terminal domains. Molecular dynamics (MD) simulations showed that 1 locks the WPD loop of hPTP1B1-400 in a closed conformation, avoiding substrate binding, products release, and catalysis, suggesting an allosteric modulation triggered by large-scale conformational and dynamics changes. Intrinsic quenching fluorescence experiments indicated that 1 behaves like a static quencher of hPTP1B1-400 (KSV = 1.1 × 105 M-1), and corroborated that it binds to the enzyme with an affinity constant (ka) of 3.7 × 105 M-1. Finally, the drug-likeness and medicinal chemistry friendliness of 1 were predicted with SwissADME.

Syntaxin 6-mediated exosome secretion regulates enzalutamide resistance in prostate cancer.

Prostate cancer (PCa) deaths are typically the result of metastatic castration-resistant PCa (mCRPC). Recently, enzalutamide (Enz), an oral androgen receptor inhibitor, was approved for treating patients with mCRPC. Invariably, all PCa patients eventually develop resistance against Enz. Therefore, novel strategies aimed at overcoming Enz resistance are needed to improve the survival of PCa patients. The role of exosomes in drug resistance has not been fully elucidated in PCa. Therefore, we set out to better understand the exosome's role in the mechanism underlying Enz-resistant PCa. Results showed that Enz-resistant PCa cells (C4-2B, CWR-R1, and LNCaP) secreted significantly higher amounts of exosomes (2-4 folds) compared to Enz-sensitive counterparts. Inhibition of exosome biogenesis in resistant cells by GW4869 and dimethyl amiloride strongly decreased their cell viability. Mechanistic studies revealed upregulation of syntaxin 6 as well as its increased colocalization with CD63 in Enz-resistant PCa cells compared to Enz-sensitive cells. Syntaxin 6 knockdown by specific small interfering RNAs in Enz-resistant PCa cells (C4-2B and CWR-R1) resulted in reduced cell number and increased cell death in the presence of Enz. Furthermore, syntaxin 6 knockdown significantly reduced the exosome secretion in both Enz-resistant C4-2B and CWR-R1 cells. The Cancer Genome Atlas analysis showed increased syntaxin 6 expressions associated with higher Gleason score and decreased progression-free survival in PCa patients. Importantly, IHC analysis showed higher syntaxin 6 expression in cancer tissues from Enz-treated patients compared to Enz naïve patients. Overall, syntaxin 6 plays an important role in the secretion of exosomes and increased survival of Enz-resistant PCa cells.

One-step partial synthesis of (±)-asperteretone B and related hPTP1B1-400 inhibitors from butyrolactone I.

Protein tyrosine phosphatase 1B (PTP1B) is a validated target for developing antiobesity, antidiabetic and anticancer drugs. Over the past years, several inhibitors of PTP1B have been discovered; however, none has been approved by the drug regulatory agencies. Interestingly, the research programs focused on discovering PTP1B inhibitors typically use truncated structures of the protein (PTP1B1-300, 1-300 amino acids), leading to the loss of valuable information about the inhibition and selectivity of ligands and repeatedly misleading the optimization of putative drug leads. Up to date, only six inhibitors of the full-length protein (hPTP1B1-400), with affinity constants ranging from 1.3 × 104 to 3.3 × 106 M-1, have been reported. Towards the discovery of new ligands of the full-length human PTP1B (hPTP1B1-400) from natural sources, herein we describe the isolation of a γ-lactone (1, butyrolactone I) from the fungus Aspergillus terreus, as well as the semisynthesis, inhibitory properties (in vitro and in silico), and the structure-activity relationship of a set of butyrolactone derivatives (1 and 2, and 6-12) as hPTP1B1-400 inhibitors, as well as the affinity constant (ka = 2.2 × 105 M-1) of the 1-hPTP1B1-400 complex, which was determined by fluorescence quenching experiments, after the inner filter effect correction.

Hydroxy-neo-Clerodanes and 5,10-seco-neo-Clerodanes from Salvia decora.

Preliminary analysis of the mass spectrometric (MS) and NMR spectroscopic data of the primary fractions from the biologically active extract of Salvia decora revealed spectra that are characteristic for neo-clerodane-type diterpenoids. MS-guided isolation of the bioactive fractions led to the isolation of three new chemical entities, including two hydroxy-neo-clerodanes (1 and 2) and one acylated 5,10-seco-neo-clerodane (3), along with three known diterpenoids (4-6), ursolic acid (7), and eupatorin (8). The structures of the new compounds were established by analysis of the 1D and 2D NMR and MS data, whereas their absolute configuration was deduced using a combination of experimental and theoretical ECD data and confirmed by X-ray crystallography (1 and 4). Furthermore, compounds 1, 3, 4, and 6-8 were evaluated as hPTP1B1-400 (human protein tyrosine phosphatase) inhibitors, where 7 showed the best activity, with an IC50 value in the lower µM range. Additionally, compound 7 was evaluated as an α-glucosidase inhibitor. The affinity constant of the 7-hPTP1B1-400 complex was determined by quenching fluorescence experiments (ka = 1.3 × 104 M-1), while the stoichiometry ratio (1:1 protein-ligand) was determined by a continuous variation method.

Dimeric phenalenones from Talaromyces sp. (IQ-313) inhibit hPTP1B1-400: Insights into mechanistic kinetics from in vitro and in silico studies.

A critical biological event that contributes to the appearance and progress of cancer and diabetes is the reversible phosphorylation of proteins, a process controlled by protein tyrosine-kinases (PTKs) and protein tyrosine-phosphatases (PTPs). Within the PTPs, PTP1B has gained significant interest since it is a validated target in drug discovery. Indeed, several PTP1B inhibitors have been developed, from both, synthesis and natural products. However, none have been approved by the FDA, due to their poor selectivity and/or pharmacokinetic properties. One of the most significant challenges to the discovery of PTP1B inhibitors (in vitro or in silico) is the use of truncated structures (PTP1B1-300), missing valuable information about the mechanisms of inhibition, and selectivity of ligands. The present study describes the biochemical characterization of a full-length PTP1B (hPTP1B1-400), as well as the description of phenalenones 1-4 and ursolic acid (5) as allosteric modulators. Compounds 1-5 showed inhibitory potential on hPTP1B1-400, with IC50 values ranging from 12.7 to 82.1 µM. Kinetic studies showed that 1 and 5 behave as mixed and non-competitive inhibitors, respectively. Circular dichroism experiments confirmed that 1 and 5 induced conformational changes to hPTP1B1-400. Further insights into the structure of hPTP1B1-400 were obtained from a homology model, which pointed out that the C-terminus (residues 301-400) is highly disordered. Molecular docking with the homologated model suggested that compounds 1 and 3-5 bind to the C-terminal domain, likely inducing conformational changes on the protein. Docking positions of compounds 1, 4, and 5 were refined with molecular dynamics simulations. Importantly, these simulations confirmed the high flexibility of the C-terminus of hPTP1B1-400, as well as the changes to its rigidity when bound to 1, 4, and 5.

Drug Leads from Endophytic Fungi: Lessons Learned via Scaled Production.

Recently, the isolation and elucidation of a series of polyhydroxyanthraquinones were reported from an organic extract of a solid phase culture of an endophytic fungus, Penicillium restrictum (strain G85). One of these compounds, ω-hydroxyemodin (1: ), showed promising quorum-sensing inhibition against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) in both in vitro and in vivo models. The initial supply of 1: was 19 mg, and this amount needed to be scaled by a factor of 30 to 50 times, in order to generate material for further in vivo studies. To do so, improvements were implemented to enhance both the fermentation of the fungal culture and the isolation of this compound, with the target of generating > 800 mg of study materials in a period of 13 wk. Valuable insights, both regarding chemistry and mycology, were gained during the targeted production of 1: on the laboratory-scale. In addition, methods were modified to make the process more environmentally friendly by judicious choice of solvents, implementing procedures for solvent recycling, and minimizing the use of halogenated solvents.

Structural Elucidation of Malonylcommunol and 6ß-Hydroxy-trans-communic Acid, Two Undescribed Diterpenes from Salvia cinnabarina. First Examples of Labdane Diterpenoids from a Mexican Salvia Species.

The aerial parts of Salvia cinnabarina afforded two undescribed labdane diterpenoids 1 and 2 (malonylcommunol and 6ß-hydroxy-trans-communic acid) along with two known labdane diterpenoids, trans-communic acid (3) and trans-communol (4). Additionally, seven known metabolites were also isolated; two isopimarane diterpenoids 5 and 6, two sesquiterpenoids identified as ß-eudesmol (7) and cryptomeridiol (8), and three aromatic compounds identified as phthalic acid (9), a mixture of tyrosol fatty acid esters (10) and the flavone salvigenine (11). While compounds compounds 1-3 showed significant inhibition of yeast α-glucosidase, compounds 2, 3 and 7 had no anti-inflammatory activity in the edema model induced by TPA. This paper is not only the first report on a wild population of Salvia cinnabarina, but also of the presence of labdane-type diterpenoids in a Mexican Salvia sp.

Prenylated Diresorcinols Inhibit Bacterial Quorum Sensing.

Current treatment options for bacterial infections are dependent on antibiotics that inhibit microbial growth and viability. These approaches result in the evolution of drug-resistant strains of bacteria. An anti-infective strategy that is less likely to lead to the development of resistance is the disruption of quorum sensing mechanisms, which are involved in promoting virulence. The goal of this study was to identify fungal metabolites effective as quorum sensing inhibitors. Three new prenylated diresorcinols (1-3), along with two known compounds, (4 R) -regiolone and decarboxycitrinone, were isolated from a freshwater fungus (Helotiales sp.) from North Carolina. Their structures were assigned on the basis of HRESIMS and NMR experiments. The structure of compound 1 was confirmed via X-ray diffraction analysis, and its absolute configuration was established by TDDFT-ECD and optical rotation calculations. Compounds 1-3 suppressed quorum sensing in a clinical isolate of methicillin-resistant Staphylococcus aureus (MRSA), with IC50 values ranging from 0.3 to 12.5 µM. These compounds represent potential leads in the development of antivirulence therapeutics.

Mycopyranone: a 8,8'-binaphthopyranone with potent anti-MRSA activity from the fungus Phialemoniopsis sp.

A new 8,8'-binaphthopyranone (mycopyranone, 1) was isolated from a solid fermentation of Phialemoniopsis sp. (fungal strain MSX61662), and the structure was elucidated via analysis of the NMR and HRESIMS data. The axial chirality of 1 was determined to be M by ECD. The central chirality at C-4/C-4' was assigned through a modified Mosher's method, while the absolute configuration at C-3/C-3' was deduced based on analysis of the 3 J H-3-H-4 values and NOESY correlations. Compound 1 was evaluated for its antimicrobial properties against Staphylococcus aureus SA1199 and a clinically relevant methicillin-resistant S. aureus strain (MRSA USA300 LAC strain AH1263). Compound 1 inhibited the growth of both strains in a concentration dependent manner with IC50 values in the low µM range. Molecular docking indicated that compound 1 binds to the FtsZ (tubulin-like) protein in the same pocket as viriditoxin (2), suggesting that 1 targets bacterial cell division.

Delitpyrones: α-Pyrone Derivatives from a Freshwater Delitschia sp.

In research focused on the discovery of new chemical diversity from freshwater fungi, a peak library was built and evaluated against a prostate cancer cell line, E006AA-hT, which was derived from an African American, as this population is disproportionately affected by prostate cancer. The chemical study of the bioactive sample accessioned as G858 (Delitschia sp.) led to the isolation of eight new α-pyrone derivatives (1:  - 7: , and 11: ), as well as the new 3S*,4S*-7-ethyl-4,8-dihydroxy-3,6-dimethoxy-3,4-dihydronaphthalen-1(2H)-one (15: ). In addition, the known compounds 5-(3-S-hydroxybutyl)-4-methoxy-6-methyl-2H-pyran-2-one (8: ), 5-(3-oxobutyl)-4-methoxy-6-methyl-2H-pyran-2-one (9: ), pyrenocine I (10: ), 5-butyl-6-(hydroxymethyl)-4-methoxy-2H-pyran-2-one (12: ), sporidesmin A (13: ), 6-ethyl-2,7-dimethoxyjuglone (14: ), artrichitin (16: ), and lipopeptide 15G256ε (17: ) were also obtained. The structures of the new compounds were elucidated using a set of spectroscopic (NMR) and spectrometric (HRMS) methods. The absolute configuration of the most abundant member of each subclass of compounds was assigned through a modified Mosher's ester method. For 15: , the relative configuration was assigned based on analysis of 3 J values. Compounds 1, 2, 5:  - 14, 16: , and 17: were evaluated against the cancer cell line E006AA-hT under hypoxic conditions, where compound 13: inhibited cell proliferation at a concentration of 2.5 µM.

Biosynthesis of Fluorinated Peptaibols Using a Site-Directed Building Block Incorporation Approach.

Synthetic biological approaches, such as site-directed biosynthesis, have contributed to the expansion of the chemical space of natural products, making possible the biosynthesis of unnatural metabolites that otherwise would be difficult to access. Such methods may allow the incorporation of fluorine, an atom rarely found in nature, into complex secondary metabolites. Organofluorine compounds and secondary metabolites have both played pivotal roles in the development of drugs; however, their discovery and development are often via nonintersecting tracks. In this context, we used the biosynthetic machinery of Trichoderma arundinaceum (strain MSX70741) to incorporate a fluorine atom into peptaibol-type molecules in a site-selective manner. Thus, fermentation of strain MSX70741 in media containing ortho- and meta-F-phenylalanine resulted in the biosynthesis of two new fluorine-containing alamethicin F50 derivatives. The fluorinated products were characterized using spectroscopic (1D and 2D NMR, including 19F) and spectrometric (HRESIMS/MSn) methods, and their absolute configurations were established by Marfey's analysis. Fluorine-containing alamethicin F50 derivatives exhibited potency analogous to the nonfluorinated parent when evaluated against a panel of human cancer cell lines. Importantly, the biosynthesis of fluorinated alamethicin F50 derivatives by strain MSX70741 was monitored in situ using a droplet-liquid microjunction-surface sampling probe coupled to a hyphenated system.

Calmodulin inhibitors from natural sources: an update.

Calmodulin (CaM) plays a central role in regulating a myriad of cellular functions in physiological and pathophysiological processes, thus representing an important drug target. In previous reviews, our group has reported relevant information regarding natural anti-CaM compounds up to 2009. Natural sources continue to provide a diverse and unique reservoir of CaM inhibitors for drug and research tool discovery. This review provides an update of natural products with reported CaM inhibitory properties, which includes around 70 natural products and some synthetic analogues, belonging to different structural classes. Most of these natural inhibitors were isolated from fungi and plants and belong to the stilbenoid, polyketide, alkaloid, and peptide structural classes. These products were discovered mainly using a fluorescence-based method on rationally designed biosensors, which are highly specific, low-cost, and selective and have short reaction times. The effect of several antimitotic drugs on Ca(2+)-hCaM is also described.

α-Glucosidase Inhibitors from a Xylaria feejeensis Associated with Hintonia latiflora.

Two new compounds, pestalotin 4'-O-methyl-ß-mannopyranoside (1) and 3S,4R-(+)-4-hydroxymellein (2), were isolated from an organic extract of a Xylaria feejeensis, which was isolated as an endophytic fungus from Hintonia latiflora. In addition, the known compounds 3S,4S-(+)-4-hydroxymellein (3), 3S-(+)-8-methoxymellein (4), and the quinone derivatives 2-hydroxy-5-methoxy-3-methylcyclohexa-2,5-diene-1,4-dione (5), 4S,5S,6S-4-hydroxy-3-methoxy-5-methyl-5,6-epoxycyclohex-2-en-1-one (6), and 4R,5R-dihydroxy-3-methoxy-5-methylcyclohexen-2-en-1-one (7) were obtained. The structures of 1 and 2 were elucidated using a set of spectroscopic and spectrometric techniques. The absolute configuration of the stereogenic centers of 1 and 2 was determined using ECD spectroscopy combined with time-dependent density functional theory calculations. In the case of 1, comparison of the experimental and theoretical (3)J6-7 coupling constants provided further evidence for the stereochemical assignments. Compounds 2 and 3 inhibited Saccharomyces cerevisiae α-glucosidase (αGHY), with IC50 values of 441 ± 23 and 549 ± 2.5 µM, respectively. Their activity was comparable to that of acarbose (IC50 = 545 ± 19 µM), used as positive control. Molecular docking predicted that both compounds bind to αGHY in a site different from the catalytic domain, which could imply an allosteric type of inhibition.

The Nicotiana tabacum UGT89A2 enzyme catalyzes the glycosylation of di- and trihydroxylated benzoic acid derivatives.

Glycosyltransferases catalyze the transfer of a glycoside group to a wide range of acceptor compounds to produce glycoconjugates with diverse biological and pharmacological activities. The present work reports the identification and biochemical characterization of Nicotiana tabacum UGT89A2 glycosyltransferase (NtUGT89A2). The enzyme is a monomer in solution that catalyzes the O-ß-glucosylation of di- and tri-hydroxylated and chlorinated derivatives of benzoic acid. NtUGT89A2 has a preference for 2,5-dihydroxybenzoic acid (2,5-DHBA) over 2,3-dihydroxybenzoic acid (2,3-DHBA) and 2,4-dihydroxybenzoic acid (2,4-DHBA). Other substrates that can be used by NtUGT89A2 include 3,4,5-trihydroxybenzoic acid and chlorinated derivatives such as 2-chloro-5-hydroxybenzoic acid (2-Cl-5-HBA). The substrates of NtUGT89A2 were identified by thermal stability experiments, where we observed a maximum increase of the thermal denaturation midpoint (Tm) of 10 °C in the presence of 2,5-DHBA and UDP-glucose. On the other hand, the highest specific activity was obtained with 2,5-DHBA (225 ± 1.7 nkat/mg). Further characterization revealed that the enzyme has a micromolar affinity for its substrates. Notably, the enzyme retains full activity after incubation at 70°C for one hour. These results provide a basis for future functional and structural studies of NtUGT89A2.

Antivirulence and antipathogenic activity of Mayan herbal remedies against Pseudomonas aeruginosa.

ETHNOPHARMACOLOGICAL RELEVANCE: The Yucatan Peninsula has a privileged wealth of vascular plants with which various Mayan herbal formulations have been developed. However, studies on their antipathogenic and antivirulence properties are scarce. AIM OF THE STUDY: Identify antivirulence properties in Mayan herbal remedies and determine their antipathogenic capacity in burn wounds infected with Pseudomonas aeruginosa. MATERIALS AND METHODS: An ethnobotanical study was conducted in Mayan communities in central and southern Quintana Roo, Mexico. Furthermore, the antipathogenic capacity of three Mayan herbal remedies was analyzed using an animal model of thermal damage and P. aeruginosa infection. Antivirulence properties were determined by inhibiting phenotypes regulated by quorum sensing (pyocyanin, biofilm, and swarming) and by the secretion of the ExoU toxin. The chemical composition of the most active herbal remedy was analyzed using molecular network analysis. RESULTS: It was found that topical administration of the remedy called "herbal soap" (HS) for eleven days maintained 100% survival of the animals, reduced establishment of the bacteria in the burn and prevented its systemic dispersion. Although no curative effect was recorded on tissue damaged by HS treatment, its herbal composition strongly reduced swarming and ExoU secretion. Through analysis of Molecular Networks, it was possible to carry out a global study of its chemical components, and identify the family of oxindole monoterpenoid alkaloids and carboline and tetrahydropyrididole alkaloids. In addition, flavonols, flavan-3-ols, and quinic acid derivatives were detected. CONCLUSIONS: The antipathogenic and antivirulence capacity of ancient Mayan remedies makes them a potential resource for developing new antibacterial therapies to treat burns infected by P. aeruginosa.

Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Syndrome: A Case Report and Review of Literature.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant genetic disorder of the small arteries that causes ischemic vascular events, subcortical dementia, behavioral changes, and migraine-like headaches. It is caused by a mutation in the NOTCH3 gene; this disease was first described in 1955 by van Bogaert. We present a 29-year-old woman who presented to the neurology department. She has no history of chronic degenerative diseases. She has been complaining of migraine-like headaches for the past six months. She has cognitive impairment with arithmetic and executive function deficits on neurological examination. Blood biometry and blood chemistry are within normal parameters in her laboratory studies. A viral panel and immunological profile were also performed and were not reactive. A lumbar puncture was performed, and the composition of the cerebrospinal fluid was within normal limits. An MRI was performed, which showed bilateral and symmetric white matter hyperintensities consistent with CADASIL syndrome. There is no specific treatment. Management of these patients is based on symptom control. Neurological sequelae have an important impact on the quality of life and mortality of these patients. For this reason, pharmacological preventive therapies have been sought with controversial evidence.