Biguanide-Vancomycin Conjugates are Effective Broad-Spectrum Antibiotics against Actively Growing and Biofilm-Associated Gram-Positive and Gram-Negative ESKAPE Pathogens and Mycobacteria.

Strategies to increase the efficacy and/or expand the spectrum of activity of existing antibiotics provide a potentially fast path to clinically address the growing crisis of antibiotic-resistant infections. Here, we report the synthesis, antibacterial efficacy, and mechanistic activity of an unprecedented class of biguanide-antibiotic conjugates. Our lead biguanide-vancomycin conjugate, V-C6-Bg-PhCl (5e), induces highly effective cell killing with up to a 2 orders-of-magnitude improvement over its parent compound, vancomycin (V), against vancomycin-resistant enterococcus. V-C6-Bg-PhCl (5e) also exhibits improved activity against mycobacteria and each of the ESKAPE pathogens, including the Gram-negative organisms. Furthermore, we uncover broad-spectrum killing activity against biofilm-associated Gram-positive and Gram-negative bacteria as well as mycobacteria not observed for clinically used antibiotics such as oritavancin. Mode-of-action studies reveal that vancomycin-like cell wall synthesis inhibition with improved efficacy attributed to enhanced engagement at vancomycin binding sites through biguanide association with relevant cell-surface anions for Gram-positive and Gram-negative bacteria. Due to its potency, remarkably broad activity, and lack of acute mammalian cell toxicity, V-C6-Bg-PhCl (5e) is a promising candidate for treating antibiotic-resistant infections and notoriously difficult-to-treat slowly growing and antibiotic-tolerant bacteria associated with chronic and often incurable infections. More generally, this study offers a new strategy (biguanidinylation) to enhance antibiotic activity and facilitate clinical entry.

Lipids Extracted from Mycobacterial Membrane and Enveloped PLGA Nanoparticles for Encapsulating Antibacterial Drugs Elicit Synergistic Antimicrobial Response against Mycobacteria.

Tuberculosis (TB) is a chronic disease caused byMycobacterium tuberculosis (Mtb), which shows a long treatment cycle often leads to drug resistance, making treatment more difficult. Immunogens present in the pathogen's cell membrane can stimulate endogenous immune responses. Therefore, an effective lipid-based vaccine or drug delivery vehicle formulated from the pathogen's cell membrane can improve treatment outcomes. Herein, we extracted and characterized lipids fromMycobacterium smegmatis, and the extracts contained lipids belonging to numerous lipid classes and compounds typically found associated with mycobacteria. The extracted lipids were used to formulate biomimetic lipid reconstituted nanoparticles (LrNs) and LrNs-coated poly(lactic-co-glycolic acid) nanoparticles (PLGA-LrNs). Physiochemical characterization and results of morphology suggested that PLGA-LrNs exhibited enhanced stability compared with LrNs. And both of these two types of nanoparticles inhibited the growth of M. smegmatis. After loading different drugs, PLGA-LrNs containing berberine or coptisine strongly and synergistically prevented the growth of M. smegmatis. Altogether, the bacterial membrane lipids we extracted with antibacterial activity can be used as nanocarrier coating for synergistic antibacterial treatment of M. smegmatis─an alternative model of Mtb, which is expected as a novel therapeutic system for TB treatment.

From Antagonism to Enhancement: Triton X-100 Surfactant Affects Phenanthrene Interfacial Biodegradation by Mycobacteria through a Shift in Uptake Mechanisms.

Polycyclic aromatic hydrocarbons (PAHs), as persistent environmental pollutants, often reside in nonaqueous-phase liquids (NAPLs). Mycobacterium sp. WY10, boasting highly hydrophobic surfaces, can adsorb to the oil-water interface, stabilizing the Pickering emulsion and directly accessing PAHs for biodegradation. We investigated the impact of Triton X-100 (TX100) on this interfacial uptake of phenanthrene (PHE) by Mycobacteria, using n-tetradecane (TET) and bis-(2-ethylhexyl) phthalate (DEHP) as NAPLs. Interfacial tension, phase behavior, and emulsion stability studies, alongside confocal laser scanning microscopy and electron microscope observations, unveiled the intricate interplay. In surfactant-free systems, Mycobacteria formed stable W/O Pickering emulsions, directly degrading PHE within the NAPLs because of their intimate contact. Introducing low-dose TX100 disrupted this relationship. Preferentially binding to the cells, the surfactant drastically increased the cell hydrophobicity, triggering desorption from the interface and phase separation. Consequently, PAH degradation plummeted due to hindered NAPL access. Higher TX100 concentrations flipped the script, creating surfactant-stabilized O/W emulsions devoid of interfacial cells. Surprisingly, PAH degradation remained efficient. This paradox can be attributed to NAPL emulsification, driven by the surfactant, which enhanced mass transfer and brought the substrate closer to the cells, despite their absence at the interface. This study sheds light on the complex effect of surfactants on Mycobacteria and PAH uptake, revealing an antagonistic effect at low concentrations that ultimately leads to enhanced degradation through emulsification at higher doses. These findings offer valuable insights into optimizing bioremediation strategies in PAH-contaminated environments.

Quantitative Microbial Risk Assessment of Antibiotic-Resistant E. coli, Legionella pneumophila, and Mycobacteria in Nonpotable Wastewater Reuse Applications.

Antibiotic-resistant bacteria (ARB) have become a major threat to public health and modern medicine. A simple death kinetics-based dose-response model (SD-DRM) was incorporated into a quantitative microbial risk assessment (QMRA) to assess the risks of exposure to reclaimed wastewater harboring antibiotic-resistant E. coli, Legionella pneumophila, and Mycobacterium avium for multiple exposure scenarios. The fractions of ARB and trace antibiotics present in the body were incorporated to demonstrate their impact on infection risks. Both ARB and antibiotic susceptible bacteria, ASB, are assumed to have the same dose-response in the absence of antibiotics but behave differently in the presence of residual antibiotics in the body. Annual risk of L. pneumophila infection exceeded the EPA 10-4 pppy (per person per year) benchmark at concentrations in reclaimed water greater than 103-104 CFU/L, depending on parameter variation. Enteropathogenic E. coli infection risks meet the EPA annual benchmark at concentrations around 105-106 total E. coli. The results illustrated that an increase in residual antibiotics from 0 to 40% of the minimum inhibitory concentration (MIC) reduced the risk by about 1 order of magnitude for E. coli but was more likely to result in an untreatable infection.

Mycobacterium marseillense bloodstream infection combined with skin fungal infection: a case report and literature review.

BACKGROUND: Non-tuberculous mycobacteria (NTM) are present widely in the natural environment and can invade the human body through the respiratory tract, gastrointestinal tract, and skin. Immunocompromised patients are particularly prone to infection, which primarily affects multiple organs, including the lungs, lymph nodes, and skin. However, cases of NTM bloodstream infections are rare. Here, we report a rare case of Mycobacterium marseillense bloodstream infection with concurrent skin fungal infection in a patient after kidney transplantation. Related literature was reviewed to enhance the understanding of this rare condition. CASE PRESENTATION: A 58-year-old male with a history of long-term steroid and immunosuppressant use after kidney transplantation presented with limb swelling that worsened over the past two months. Physical examination revealed redness and swelling of the skin in all four limbs, with a non-healing wound on the lower left limb. Skin tissue analysis by metagenomic next-generation sequencing (mNGS) and fungal culture indicated infection with Trichophyton rubrum. Blood culture results suggested infection with Mycobacterium marseillense. After receiving anti-NTM treatment, the patient's symptoms significantly improved, and he is currently undergoing treatment. CONCLUSION: Mycobacterium marseillense is a NTM. Gram staining suffered from misdetection, and the acid-fast staining result was positive. This bacterium was identified by mass spectrometry and mNGS analyses. Antimicrobial susceptibility tests for NTM were performed using the broth microdilution method. The results of the susceptibility test showed that Mycobacterium marseillense was sensitive to clarithromycin, an intermediary between moxifloxacin and linezolid. Bacterial clearance requires a combination of drugs and an adequate course of treatment. NTM bloodstream infections are relatively rare, and early identification and proactive intervention are key to their successful management.

Drug repositioning identifies histone deacetylase inhibitors that promote innate immunity in non-tuberculous mycobacterial infection.

Non-tuberculosis infections in immunocompromised patients represent a cause for concern, given the increased risks of infection, and limited treatments available. Herein, we report that molecules for binding to the catalytic site of histone deacetylase (HDAC) inhibit its activity, thus increasing the innate immune response against environmental mycobacteria. The action of HDAC inhibitors (iHDACs) was explored in a model of type II pneumocytes and macrophages infection by Mycobacterium aurum. The results show that the use of 1,3-diphenylurea increases the expression of the TLR-4 in M. aurum infected MDMs, as well as the production of defb4, IL-1ß, IL-12, and IL-6. Moreover, we observed that aminoacetanilide upregulates the expression of TLR-4 together with TLR-9, defb4, CAMP, RNase 6, RNase 7, IL-1ß, IL-12, and IL-6 in T2P. Results conclude that the tested iHDACs selectively modulate the expression of cytokines and antimicrobial peptides that are associated with reduction of non-tuberculous mycobacteria infection.

Effects of Graphene Oxide on Endophytic Bacteria Population Characteristics in Plants from Soils Contaminated by Polycyclic Aromatic Hydrocarbons.

Environmental pollution stands as one of the significant global challenges we face today. Polycyclic aromatic hydrocarbons (PAHs), a class of stubborn organic pollutants, have long been a focal point of bioremediation research. This study aims to explore the impact and mechanisms of graphene oxide (GO) on the phytoremediation effectiveness of PAHs. The results underscore the significant efficacy of GO in accelerating the degradation of PAHs. Additionally, the introduction of GO altered the diversity and community structure of endophytic bacteria within the roots, particularly those genera with potential for PAH degradation. Through LEfSe analysis and correlation studies, we identified specific symbiotic bacteria, such as Mycobacterium, Microbacterium, Flavobacterium, Sphingomonas, Devosia, Bacillus, and Streptomyces, which coexist and interact under the influence of GO, synergistically degrading PAHs. These bacteria may serve as key biological markers in the PAH degradation process. These findings provide new theoretical and practical foundations for the application of nanomaterials in plant-based remediation of polluted soils and showcase the immense potential of plant-microbe interactions in environmental restoration.

Plasmid-mediated drug resistance in mycobacteria: the tip of the iceberg?

Macrolides, such as clarithromycin, are crucial in the treatment of nontuberculous mycobacteria (NTM). NTM are notoriously innately drug resistant, which has made the dependence on macrolides for their treatment even more important. Not surprisingly, resistance to macrolides has been documented in some NTM, including Mycobacterium avium and Mycobacterium abscessus, which are the two NTM species most often identified in clinical isolates. Resistance is mediated by point mutations in the 23S ribosomal RNA or by methylation of the rRNA by a methylase (encoded by an erm gene). Chromosomally encoded erm genes have been identified in many of the macrolide-resistant isolates, but not in Mycobacterium chelonae. Now, Brown-Elliott et al. (J Clin Microbiol 61:e00428-23, 2023, https://doi.org/10.1128/JCM.00428-23) describe the identification of a new erm variant, erm(55), which was found either on the chromosome or on a plasmid in highly macrolide-resistant clinical isolates of M. chelonae. The chromosomal erm(55) gene appears to be associated with mobile elements; one gene is within a putative transposon and the second is in a large (37 kb) insertion/deletion. The plasmid carrying erm(55) also encodes type IV and type VII secretion systems, which are often linked on large mycobacterial plasmids and are hypothesized to mediate plasmid transfer. While the conjugative transfer of the erm(55)-containing plasmid between NTM has yet to be demonstrated, the inferences are clear, as evidenced by the dissemination of plasmid-mediated drug resistance in other medically important bacteria. Here, we discuss the findings of Brown-Elliott et al., and the potential ramifications on treatment of NTM infections.

Structural basis for the broad substrate specificity of two acyl-CoA dehydrogenases FadE5 from mycobacteria.

FadE, an acyl-CoA dehydrogenase, introduces unsaturation to carbon chains in lipid metabolism pathways. Here, we report that FadE5 from Mycobacterium tuberculosis (MtbFadE5) and Mycobacterium smegmatis (MsFadE5) play roles in drug resistance and exhibit broad specificity for linear acyl-CoA substrates but have a preference for those with long carbon chains. Here, the structures of MsFadE5 and MtbFadE5, in the presence and absence of substrates, have been determined. These reveal the molecular basis for the broad substrate specificity of these enzymes. FadE5 interacts with the CoA region of the substrate through a large number of hydrogen bonds and an unusual π-π stacking interaction, allowing these enzymes to accept both short- and long-chain substrates. Residues in the substrate binding cavity reorient their side chains to accommodate substrates of various lengths. Longer carbon-chain substrates make more numerous hydrophobic interactions with the enzyme compared with the shorter-chain substrates, resulting in a preference for this type of substrate.

Progress on the non-canonical mismatch repair in Mycobacterium and its role in antibiotic resistance.

Mismatch repair (MMR) is a common repair system after DNA replication, which is critical for maintaining genomic stability. Members of the MutS and MutL protein families are involved in key steps of mismatch repair. Despite the major importance of this repair pathway, MutS-MutL are absent in almost all Actinobacteria and many Archaea. Mycobacteria and others have another non-canonical MMR pathway, in which EndoMS/NucS plays a key role and has no structural homology compared to canonical MMR proteins (MutS/MutL). EndoMS/NucS mediated non-canonical mismatch repair plays an important role in DNA repair, mutation, homologous recombination and antibiotic resistance of Mycobacterium. By comparing the classical and non-canonical MMR pathways, this paper reviews the EndoMS/NucS-mediated non-canonical MMR pathway in Mycobacterium and its recent progress. We hope to bring new insights into the molecular mechanism of mycobacterial mismatch repair as well as to provide new research clues for mycobacterial antibiotic therapy.

Gwanakosides A and B, 6-Deoxy-α-l-talopyranose-Bearing Aromatic Metabolites from a Streptomyces sp. and Coculture with Pandoraea sp.

Single-strain cultivation of a mountain soil-derived Streptomyces sp. GA02 and its coculture with Pandoraea sp. GA02N produced two aromatic products, gwanakosides A and B (1 and 2, respectively). Their spectroscopic analysis revealed that 1 is a new dichlorinated naphthalene glycoside and 2 is a pentacyclic aromatic glycoside. The assignment of the two chlorine atoms in 1 was confirmed by the analysis of its band-selective CLIP-HSQMBC spectrum. The sugars in the gwanakosides were identified as 6-deoxy-α-l-talopyranose based on 1H-1H coupling constants, Rotating frame Overhauser enhancement spectroscopy (ROESY) NMR correlations, and chemical derivatization followed by spectroscopic and chromatographic analyses. The absolute configuration of 2, whose production was enhanced approximately 100-fold in coculture, was proposed based on a quantum mechanics-based chemical shift analysis method, DP4 calculations, and the chemically determined configuration of 6-deoxy-α-l-talopyranose. Gwanakoside A displayed inhibitory activity against pathogenic bacteria, including Staphylococcus aureus (MIC = 8 µg/mL) and Mycobacterium tuberculosis (MIC50 = 15 µg/mL), and antiproliferative activity against several human cancer cell lines (IC50 = 5.6-19.4 µM).

Antibacterial Activity of Pharmaceutical-Grade Rose Bengal: An Application of a Synthetic Dye in Antibacterial Therapies.

Rose bengal has been used in the diagnosis of ophthalmic disorders and liver function, and has been studied for the treatment of solid tumor cancers. To date, the antibacterial activity of rose bengal has been sporadically reported; however, these data have been generated with a commercial grade of rose bengal, which contains major uncontrolled impurities generated by the manufacturing process (80-95% dye content). A high-purity form of rose bengal formulation (HP-RBf, >99.5% dye content) kills a battery of Gram-positive bacteria, including drug-resistant strains at low concentrations (0.01-3.13 µg/mL) under fluorescent, LED, and natural light in a few minutes. Significantly, HP-RBf effectively eradicates Gram-positive bacterial biofilms. The frequency that Gram-positive bacteria spontaneously developed resistance to HP-RB is extremely low (less than 1 × 10-13). Toxicity data obtained through our research programs indicate that HP-RB is feasible as an anti-infective drug for the treatment of skin and soft tissue infections (SSTIs) involving multidrug-resistant (MDR) microbial invasion of the skin, and for eradicating biofilms. This article summarizes the antibacterial activity of pharmaceutical-grade rose bengal, HP-RB, against Gram-positive bacteria, its cytotoxicity against skin cells under illumination conditions, and mechanistic insights into rose bengal's bactericidal activity under dark conditions.

Ribosome hibernation: a new molecular framework for targeting nonreplicating persisters of mycobacteria.

Treatment of tuberculosis requires a multi-drug regimen administered for at least 6 months. The long-term chemotherapy is attributed in part to a minor subpopulation of nonreplicating Mycobacterium tuberculosis cells that exhibit phenotypic tolerance to antibiotics. The origins of these cells in infected hosts remain unclear. Here we discuss some recent evidence supporting the hypothesis that hibernation of ribosomes in M. tuberculosis, induced by zinc starvation, could be one of the primary mechanisms driving the development of nonreplicating persisters in hosts. We further analyse inconsistencies in previously reported studies to clarify the molecular principles underlying mycobacterial ribosome hibernation.

Point mutation in the stop codon of MAV_RS14660 increases the growth rate of Mycobacterium avium subspecies hominissuis.

Mycobacterium avium subspecies hominissuis (MAH) is a pathogen that causes various non-tuberculous mycobacterial diseases in humans and animals worldwide. Among the genus, MAH is characterized by relatively slow growth. Here, we isolated a rapidly growing variant of the MAH 104 strain. The variant strain (named N104) exhibited an enhanced growth rate and higher motility compared to the parent MAH 104 strain (P104). Whole-genome sequencing analysis of N104 revealed the loss of the stop codon of MAV_RS14660 due to a single nucleotide replacement, resulting in the substitution of the codon for tryptophan. Notably, exclusion of the stop codon ligated the open reading frames and caused the fusion of two adjacent proteins. A revertant parent strain, in which a mutation was introduced to restore the stop codon, revealed that elimination of the stop codon in MAV_RS14660 was responsible for the N104 phenotype. Furthermore, we analysed the phenotypes of the parent and mutated strains by determining the functions of the MAV_RS14660 and MAV_RS14655 coding regions flanking the stop codon. The mutant strains, expected to express a fusion protein, exhibited increased resistance to antimicrobial drugs and exogenous copper toxicity compared to that of the parent strains. These findings suggest that the fusion of the MAV_RS14660- and MAV_RS14655-encoding regions in the mutant N104 strain could be related to the modified functions of these intrinsic proteins.

Ligand Induced CuII Transport Restricts Cancer and Mycobacterial Growth: Towards a Plug-and-Select Ion Channel Scaffold.

Synthetic channels with high ion selectivity are attractive drug targets for diseases involving ion dysregulation. Achieving selective transport of divalent ions is highly challenging due their high hydration energies. A small tripeptide amphiphilic scaffold installed with a pybox ligand selectively transports CuII ions across membranes. The peptide forms stable dimeric pores in the membrane and transports ions by a Cu2+ /H+ antiport mechanism. The ligand-induced excellent CuII selectivity as well as high membrane permeability of the peptide is exploited to promote cancer cell death. The peptide's ability to restrict mycobacterial growth serves as seeds to evolve antibacterial strategies centred on selectively modulating ion homeostasis in pathogens. This simple peptide can potentially function as a universal, yet versatile, scaffold wherein the ion selectivity can be precisely controlled by modifying the ligand at the C terminus.

Airborne Disinfection by Dry Fogging Efficiently Inactivates Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Mycobacteria, and Bacterial Spores and Shows Limitations of Commercial Spore Carriers.

Airborne disinfection of high-containment facilities before maintenance or between animal studies is crucial. Commercial spore carriers (CSC) coated with 106 spores of Geobacillus stearothermophilus are often used to assess the efficacy of disinfection. We used quantitative carrier testing (QCT) procedures to compare the sensitivity of CSC with that of surrogates for nonenveloped and enveloped viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), mycobacteria, and spores, to an aerosolized mixture of peroxyacetic acid and hydrogen peroxide (aPAA-HP). We then used the QCT methodology to determine relevant process parameters to develop and validate effective disinfection protocols (≥4-log10 reduction) in various large and complex facilities. Our results demonstrate that aPAA-HP is a highly efficient procedure for airborne room disinfection. Relevant process parameters such as temperature and relative humidity can be wirelessly monitored. Furthermore, we found striking differences in inactivation efficacies against some of the tested microorganisms. Overall, we conclude that dry fogging a mixture of aPAA-HP is highly effective against a broad range of microorganisms as well as material compatible with relevant concentrations. Furthermore, CSC are artificial bioindicators with lower resistance and thus should not be used for validating airborne disinfection when microorganisms other than viruses have to be inactivated.IMPORTANCE Airborne disinfection is not only of crucial importance for the safe operation of laboratories and animal rooms where infectious agents are handled but also can be used in public health emergencies such as the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. We show that dry fogging an aerosolized mixture of peroxyacetic acid and hydrogen peroxide (aPAA-HP) is highly microbicidal, efficient, fast, robust, environmentally neutral, and a suitable airborne disinfection method. In addition, the low concentration of dispersed disinfectant, particularly for enveloped viral pathogens such as SARS-CoV-2, entails high material compatibility. For these reasons and due to the relative simplicity of the procedure, it is an ideal disinfection method for hospital wards, ambulances, public conveyances, and indoor community areas. Thus, we conclude that this method is an excellent choice for control of the current SARS-CoV-2 pandemic.

Emerging MDR-Mycobacterium avium subsp. avium in house-reared domestic birds as the first report in Egypt.

BACKGROUND: Avian tuberculosis is a chronic and zoonotic disease that affects a wide variety of birds, mammals, and humans. This study aimed to estimate the frequency of Mycobacterium avium subsp. avium in some domestic birds based on molecular diagnosis, antibiogram profile, and PCR-based detection of inhA, rpoB, rpsL, and otrB antibiotic resistance-related genes. METHODS: A total of 120 fecal samples were collected from small flocks of house-reared domestic birds at Ismailia Governorate, Egypt. The collected samples were processed and subjected to the bacteriological examination. The antimicrobial susceptibility testing of the recovered isolates was performed using the broth microdilution method for the detection of minimum inhibitory concentrations (MICs). The genetic detection of the IS901confirmatory gene, inhA, rpoB, rpsL, and otrB genes was carried out using PCR. RESULTS: The frequency of M. avium subsp. avium was 4.1% (5/120); 10% (4/40) in ducks, and 2.5% (1/10) in geese. The identification of the recovered isolates was confirmed using PCR, where all the tested isolates were positive for IS901confirmatory gene. The results of the broth microdilution method revealed that most of the recovered isolates exhibited multidrug resistance (MDR) to isoniazid, rifampicin, streptomycin, oxytetracycline, and doxycycline, and harbored the inhA, rpoB, rpsL, and otrB genes. CONCLUSION: In brief, to the best of our knowledge this is the first report that emphasized the emergence of avian tuberculosis in house-reared domestic birds in Egypt. The emergence of MDR- M. avium subsp. avium is considered a public health threat. Emerging MDR-M. avium subsp. avium in domestic birds are commonly harbored the IS901, inhA, rpoB, rpsL, and otrB genes. Azithromycin and clofazimine revealed a promising in-vitro antibacterial activity against M. avium subsp. avium.

Racemization-free synthesis of Nα-2-thiophenoyl-phenylalanine-2-morpholinoanilide enantiomers and their antimycobacterial activity.

Nα-2-thiophenoyl-D-phenylalanine-2-morpholinoanilide (MMV688845, IUPAC: N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide) from the Pathogen Box® library (Medicines for Malaria Ventures, MMV) is a promising lead compound for antimycobacterial drug development. Two straightforward synthetic routes to the title compound starting from phenylalanine or its Boc-protected derivative are reported. Employing Boc-phenylalanine as starting material and the T3P® and PyBOP® amide coupling reagents enables racemization-free synthesis, avoiding the need for subsequent separation of the enantiomers. The crystal structure of the racemic counterpart gives insight into the molecular structure and hydrogen bonding interactions in the solid state. The R-enantiomer of the title compound (derived from D-phenylalanine) exhibits activity against non-pathogenic and pathogenic mycobacterial strains, whereas the S-enantiomer is inactive. Neither of the enantiomers and the racemate of the title compound shows cytotoxicity against various mammalian cells.

Antimicrobial Benzyltetrahydroisoquinoline-Derived Alkaloids from the Leaves of Doryphora aromatica.

Four new alkaloids, (R)-nomimantharine trifluoroacetate (2), 12-demethylphaeantharine trifluoroacetate (3), nominanthranal trifluoroacetate (4), and the enolic form of 1-hydroxy-6,7-dimethoxy-2-methylisoquinoline trifluoroacetate (5), together with the known dimeric alkaloid phaeantharine trifluoroacetate (1), have been isolated from the extract of the leaves of the rainforest tree Doryphora aromatica (Monimiaceae). The structures of these compounds were elucidated by HRMS and 1D and 2D NMR data. (R)-Nomimantharine trifluoroacetate (2) contains an ether linkage connecting a benzylisoquinoline unit with a tetrahydroisoquinoline, a novel class of dimeric alkaloid. The absolute configuration of (R)-nomimantharine trifluoroacetate (2) was established via electronic circular dichroism data. The compounds isolated were subjected to in vitro antimicrobial assays against a panel of pathogenic microorganisms, including Mycobacterium smegmatis, M. tuberculosis, Escherichia coli, Staphylococcus aureus (SA), and five clinical isolates of oxacillin/methicillin-resistant S. aureus (MRSA). Phaeantharine trifluoroacetate (1) and (R)-nomimantharine trifluoroacetate (2) showed moderate inhibitory activities against Mycobacteria and MRSA strains.

Marine Antibiotics 2020.

The range of environmental conditions in marine life is tremendous at different physico-chemical criteria (temperature, light, pressure and salinity) [...].