Fitness trade-offs of multidrug efflux pumps in Escherichia coli K-12 in acid or base, and with aromatic phytochemicals.

Multidrug efflux pumps are the frontline defense mechanisms of Gram-negative bacteria, yet little is known of their relative fitness trade-offs under gut conditions such as low pH and the presence of antimicrobial food molecules. Low pH contributes to the proton-motive force (PMF) that drives most efflux pumps. We show how the PMF-dependent pumps AcrAB-TolC, MdtEF-TolC, and EmrAB-TolC undergo selection at low pH and in the presence of membrane-permeant phytochemicals. Competition assays were performed by flow cytometry of co-cultured Escherichia coli K-12 strains possessing or lacking a given pump complex. All three pumps showed negative selection under conditions that deplete PMF (pH 5.5 with carbonyl cyanide 3-chlorophenylhydrazone or at pH 8.0). At pH 5.5, selection against AcrAB-TolC was increased by aromatic acids, alcohols, and related phytochemicals such as methyl salicylate. The degree of fitness cost for AcrA was correlated with the phytochemical's lipophilicity (logP). Methyl salicylate and salicylamide selected strongly against AcrA, without genetic induction of drug resistance regulons. MdtEF-TolC and EmrAB-TolC each had a fitness cost at pH 5.5, but salicylate or benzoate made the fitness contribution positive. Pump fitness effects were not explained by gene expression (measured by digital PCR). Between pH 5.5 and 8.0, acrA and emrA were upregulated in the log phase, whereas mdtE expression was upregulated in the transition-to-stationary phase and at pH 5.5 in the log phase. Methyl salicylate did not affect pump gene expression. Our results suggest that lipophilic non-acidic molecules select against a major efflux pump without inducing antibiotic resistance regulons.IMPORTANCEFor drugs that are administered orally, we need to understand how ingested phytochemicals modulate drug resistance in our gut microbiome. Bacteria maintain low-level resistance by proton-motive force (PMF)-driven pumps that efflux many different antibiotics and cell waste products. These pumps play a key role in bacterial defense by conferring resistance to antimicrobial agents at first exposure while providing time for a pathogen to evolve resistance to higher levels of the antibiotic exposed. Nevertheless, efflux pumps confer energetic costs due to gene expression and pump energy expense. The bacterial PMF includes the transmembrane pH difference (ΔpH), which may be depleted by permeant acids and membrane disruptors. Understanding the fitness costs of efflux pumps may enable us to develop resistance breakers, that is, molecules that work together with antibiotics to potentiate their effect. Non-acidic aromatic molecules have the advantage that they avoid the Mar-dependent induction of regulons conferring other forms of drug resistance. We show that different pumps have distinct selection criteria, and we identified non-acidic aromatic molecules as promising candidates for drug resistance breakers.

Complementation testing identifies causal genes at quantitative trait loci underlying fear related behavior.

Knowing the genes involved in quantitative traits provides a critical entry point to understanding the biological bases of behavior, but there are very few examples where the pathway from genetic locus to behavioral change is known. Here we address a key step towards that goal by deploying a test that directly queries whether a gene mediates the effect of a quantitative trait locus (QTL). To explore the role of specific genes in fear behavior, we mapped three fear-related traits, tested fourteen genes at six QTLs, and identified six genes. Four genes, Lsamp, Ptprd, Nptx2 and Sh3gl, have known roles in synapse function; the fifth gene, Psip1, is a transcriptional co-activator not previously implicated in behavior; the sixth is a long non-coding RNA 4933413L06Rik with no known function. Single nucleus transcriptomic and epigenetic analyses implicated excitatory neurons as likely mediating the genetic effects. Surprisingly, variation in transcriptome and epigenetic modalities between inbred strains occurred preferentially in excitatory neurons, suggesting that genetic variation is more permissible in excitatory than inhibitory neuronal circuits. Our results open a bottleneck in using genetic mapping of QTLs to find novel biology underlying behavior and prompt a reconsideration of expected relationships between genetic and functional variation.

Talcarpones A and B: bisnaphthazarin-derived metabolites from the Australian fungus Talaromyces johnpittii sp. nov. MST-FP2594.

Talcarpones A (1) and B (2) are rare bisnaphthazarin derivatives produced by Talaromyces johnpittii (ex-type strain MST-FP2594), a newly discovered Australian fungus, which is formally described and named herein. The talcarpones were isolated along with the previously reported monomeric naphthoquinone, aureoquinone (3), suggesting a biosynthetic link between these metabolites. Talcarpone A is a lower homologue of hybocarpone (4), which was first isolated from a mycobiont of the lichen Lecanora hybocarpa. The structures of 1 and 2 were elucidated by detailed spectroscopic analysis, molecular modelling and comparison with literature data. Talcarpones 1 and 2 exhibited moderate antifungal activity (MIC 0.78-3.1 µg ml-1) and weak activity against Gram-positive bacteria (MIC 13-25 µg ml-1). The talcarpones also demonstrated noteworthy chemical reactivities, with 2 converting rapidly to 1, which in turn converted slowly to the highly coloured 3. These post-biosynthetic reactions point to a potential ecological role for the talcarpones in providing ongoing (slow-release) physicochemical protection for T. johnpittii against solar irradiation.

Fungal Duel between Penicillium brasilianum and Aspergillus nomius Results in Dual Induction of Miktospiromide A and Kitrinomycin A.

Cocultivation of the fungi Penicillium brasilianum MST-FP1927 and Aspergillus nomius MST-FP2004 resulted in the reciprocal induction of two new compounds, miktospiromide A (1) from A. nomius and kitrinomycin A (2) from P. brasilianum. A third new compound, kitrinomycin B (3), was also identified from an axenic culture of P. brasilianum, along with the previously reported compounds austalide K (4), 17S-dihydroaustalide K (5), verruculogen (6), and fumitremorgin B (7). The structures of 1-3 were elucidated by detailed spectroscopic analysis and DFT calculations, while 4-7 were identified by comparison to authentic standards. The genome of A. nomius MST-FP2004 was sequenced, and a putative biosynthetic gene cluster for 1 was identified. Compound 2 showed activity against murine melanoma NS-1 cells (LD99 7.8 µM) and the bovine parasite Tritrichomonas foetus (LD99 4.8 µM).

Turonicin A, an Antifungal Linear Polyene Polyketide from an Australian Streptomyces sp.

Turonicin A (1) was isolated from Streptomyces sp. MST-123921, which was recovered from soil collected on the banks of the Turon River in New South Wales, Australia. Turonicin A (1) is an amphoteric linear polyene polyketide featuring independent pentaene and tetraenone chromophores and is structurally related to linearmycins A-C (2-4). The structure of 1 was determined by detailed spectroscopic analysis and comparison to literature data. Bioinformatic analysis of the linearmycin biosynthetic gene cluster also allowed the previously unresolved absolute stereostructures of 2-4 to be elucidated. Turonicin A (1) exhibited very potent activity against the fungi Candida albicans (MIC 0.0031 µg/mL, 2.7 nM) and Saccharomyces cerevisiae (MIC 0.0008 µg/mL, 0.7 nM), moderate activity against the bacteria Bacillus subtilis (MIC 0.097 µg/mL, 85 nM) and Staphylococcus aureus (MIC 0.39 µg/mL, 340 nM), and no cytotoxicity against human fibroblasts, making it an attractive candidate for further development as a potential next-generation antibiotic scaffold.

The vicious cycle of psychopathology and stressful life events: A meta-analytic review testing the stress generation model.

Stress generation theory initially posited that depression elevates risk for some stressful events (i.e., dependent events) but not others (i.e., independent events). This preregistered meta-analytic review examined whether stress generation occurs transdiagnostically by examining 95 longitudinal studies with 38,228 participants (537 total effect sizes) from over 30 years of research. Our multilevel meta-analyses found evidence of stress generation across a broad range of psychopathology, as evidenced by significantly larger prospective effects for dependent (overall psychopathology: r = .23) than independent (overall psychopathology: r = .10) stress. We also identified unique patterns of effects across specific types of psychopathology. For example, effects were larger for depression than anxiety. Furthermore, effects were sometimes larger in studies with younger participants, shorter time lags between assessments, checklist measures of stress, and for interpersonal stressors. Finally, a multilevel meta-analytic structural equation model suggested that dependent stress exacerbates psychopathology symptoms over time (ß = .04), possibly contributing to chronicity. Interventions targeting the prevention of stress generation may mitigate chronic psychopathology. Conclusions of this study are limited by the predominance of depression effect sizes in the literature and our review of only English language articles. On the other hand, the findings are strengthened by rigorous inclusion criteria, lack of publication bias, and absence of moderating effects by publication year. The latter underscores the replicability of the stress generation effect over the last 30 years. Taken together, the review provides robust evidence that stress generation is a cross-diagnostic phenomenon that contributes to a vicious cycle of increasing stress and psychopathology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Risk and protective factors for stress generation: A meta-analytic review.

The stress generation hypothesis suggests that some individuals contribute more than others to the occurrence of dependent (self-generated), but not independent (fateful), stressful life events. This phenomenon is commonly studied in relation to psychiatric disorders, but effects are also driven by underlying psychological processes that extend beyond the boundaries of DSM-defined entities. This meta-analytic review of modifiable risk and protective factors for stress generation synthesizes findings from 70 studies with 39,693 participants (483 total effect sizes) from over 30 years of research. Findings revealed a range of risk factors that prospectively predict dependent stress with small-to-moderate meta-analytic effects (rs = 0.10-0.26). Negligible to small effects were found for independent stress (rs = 0.03-0.12), and, in a critical test for stress generation, most effects were significantly stronger for dependent compared to independent stress (ßs = 0.04-0.15). Moderation analyses suggest effects of maladaptive interpersonal emotion regulation behaviors and repetitive negative thinking are stronger for interpersonal (versus non-interpersonal) stress; effects of repetitive negative thinking and excessive standards for self may be inflated by overreliance on self-report measures that fail to isolate psychological distress from objective experience. Findings have key implications for advancing stress generation theory and informing targets for intervention.

Resorculins: hybrid polyketide macrolides from Streptomyces sp. MST-91080.

Fourteen-membered macrolides are a class of compounds with significant clinical value as antibacterial agents. As part of our ongoing investigation into the metabolites of Streptomyces sp. MST-91080, we report the discovery of resorculins A and B, unprecedented 3,5-dihydroxybenzoic acid (α-resorcylic acid)-containing 14-membered macrolides. We sequenced the genome of MST-91080 and identified the putative resorculin biosynthetic gene cluster (rsn BGC). The rsn BGC is hybrid of type I and type III polyketide synthases. Bioinformatic analysis revealed that the resorculins are relatives of known hybrid polyketides: kendomycin and venemycin. Resorculin A exhibited antibacterial activity against Bacillus subtilis (MIC 19.8 µg mL-1), while resorculin B showed cytotoxic activity against the NS-1 mouse myeloma cell line (IC50 3.6 µg mL-1).

Evaluation of Low- and Middle-Income Country Authorship in the Global Orthopaedic Literature.

INTRODUCTION: Extensive research collaborations exist between high-income countries and low- and middle-income countries (LMICs), although prior work has raised concerns regarding equitable representation among LMIC authors. The goal of this bibliometric analysis was to characterize LMIC authorship among indexed orthopaedic journals and identify factors contributing to disparities in representation. METHODS: We identified all articles appearing in orthopaedic journals indexed in MEDLINE and Journal Citation Reports with a focus on LMICs or cohorts between 2009 and 2018. All articles describing research conducted in LMICs or research focused on applications to cohorts in LMIC(s) were included. Author affiliation, article characteristics, and impact factor were assessed for 1,573 articles. Logistic regression models created to identify predictors of LMIC authorship. RESULTS: We identified few studies published in indexed journals focused exclusively on LICs. Funded studies were less likely to have LMIC last authors. Compared with articles published in lower impact factor journals, those in journals with a higher impact factor were less likely to have a LMIC first or last author. The greater the number of countries represented per study, the less likely it had a LMIC first or last author. CONCLUSION: Our study highlights persistent disparities in authorship from LMICs in indexed orthopaedic journals.

Longitudinal efficacy and toxicity of SARS-CoV-2 vaccination in cancer patients treated with immunotherapy.

Despite more than 2 years having elapsed since the onset of SARS-CoV-2 pandemic, a level of hesitation around increased SARS-CoV-2 vaccine toxicity in cancer patients receiving immunotherapy (IO) remains. This hesitation stems from the idea that IO agents could elicit an overwhelming immune stimulation post vaccination and therefore increase the risk of vaccine-related toxicity. The aim of our study was to explore serological responses to SARS-CoV-2 vaccination in patients treated with IO and describe the level of immune stimulation using parameters such as blood cytokines, autoantibody levels and immune related adverse events (irAEs) post vaccination. Fifty-one evaluable patients were enrolled in this longitudinal study. Absolute levels and neutralization potential of anti-SARS-CoV-2 antibodies were not significantly different in the IO group compared to non-IO. Chemotherapy adversely affected seroconversion when compared to IO and/or targeted treatment. Following vaccination, the prevalence of grade ≥2 irAEs in patients treated with IO was not higher than the usual reported IO toxicity. We report, for the first time, that anti-SARS-CoV-2 vaccination, elicited the generation of five autoantibodies. The significantly increased autoantibodies were IgM autoantibodies against beta-2 glycoprotein (p = 0.02), myeloperoxidase (p = 0.03), nucleosome (p = 0.041), SPLUNC2 (p < 0.001) and IgG autoantibody against Myosin Heavy Chain 6 (MYH6) (p < 0.001). Overall, comprehensive analysis of a small cohort showed that co-administration of SARS-CoV-2 vaccine and IO is not associated with increased irAEs. Nevertheless, the detection of autoantibodies post anti-SARS-CoV-2 vaccination warrants further investigation (NCT03702309).

A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients.

The molecular underpinnings of organ dysfunction in acute COVID-19 and its potential long-term sequelae are under intense investigation. To shed light on these in the context of liver function, we performed single-nucleus RNA-seq and spatial transcriptomic profiling of livers from 17 COVID-19 decedents. We identified hepatocytes positive for SARS-CoV-2 RNA with an expression phenotype resembling infected lung epithelial cells. Integrated analysis and comparisons with healthy controls revealed extensive changes in the cellular composition and expression states in COVID-19 liver, reflecting hepatocellular injury, ductular reaction, pathologic vascular expansion, and fibrogenesis. We also observed Kupffer cell proliferation and erythrocyte progenitors for the first time in a human liver single-cell atlas, resembling similar responses in liver injury in mice and in sepsis, respectively. Despite the absence of a clinical acute liver injury phenotype, endothelial cell composition was dramatically impacted in COVID-19, concomitantly with extensive alterations and profibrogenic activation of reactive cholangiocytes and mesenchymal cells. Our atlas provides novel insights into liver physiology and pathology in COVID-19 and forms a foundational resource for its investigation and understanding.

A risk stratification model for toxicities in phase 1 immunotherapy trials.

INTRODUCTION: Despite the increased number of novel immunotherapy (IO) agents under current development, their toxicity profile remains to be fully elucidated. METHODS: An IO risk stratification model was developed based on 5 different variables: treatment-related deaths; rate of grade ≥3 treatment-related adverse events or treatment-emergent adverse events; grade ≥2 encephalopathy or central nervous system toxicity; grade ≥2 cytokine release syndrome; and the number and type of dose-limiting toxicity. Phase 1 IO trials published from January 2014 to December 2020 were reviewed and categorised based on our risk stratification model into three categories: low-, intermediate- and high-risk. Clinical trial variables were associated with the high-risk category. To review the quality of reporting across phase 1 IO trials, a subset of studies was further examined by the use of the ASCO/SITC Trial Reporting in Immuno-Oncology (TRIO) standards. RESULTS: Different IO compounds demonstrated diverse risk profiles. In multivariable analysis, combination versus IO single agent treatment, and testing IO agents different from anti-programmed death-1/programmed death ligand-1 (anti-PD1/L1), anti-cytotoxic t-lymphocyte antigen-4 (anti-CTLA4) antibodies and anti-cancer vaccines were associated with a higher toxicity risk. None of the studies examined in our dataset reported all the items included in the TRIO standards. CONCLUSIONS: Our results have important implications for future clinical trial design. Additionally, standards for reporting are urgently needed.

Impact of pharmacodynamic biomarkers in immuno-oncology phase 1 clinical trials.

BACKGROUND: Phase 1 immuno-oncology (IO) trials frequently involve pharmacodynamic (PD) biomarker assessments involving tumour biopsies and/or blood collection, with increasing use of molecular imaging. PD biomarkers are set to play a fundamental role in early drug development of immuno-oncology (IO) agents. In the IO era, the impact of PD biomarkers for confirmation of biologic activity and their role in subsequent drug development have not been investigated. METHODS: Phase 1 studies published between January 2014 and December 2020 were reviewed. Studies that reported on-treatment PD biomarkers [tissue-derived (tissue-PD), blood-based (blood-PD) and imaging-based (imaging-PD)] were analysed. PD biomarker results and their correlation with clinical activity endpoints were evaluated. Authors' statements on the influence of PD biomarkers on further drug development decisions, and subsequent citations of PD biomarker study results were recorded. RESULTS: Among 386 trials, the most frequent IO agent classes evaluated were vaccines (32%) and PD-(L)1 inhibitors (25%). No PD biomarker assessments were reported in 100 trials (26%). Of the remaining 286, blood-PD, tissue-PD, and imaging-PD data were reported in 270 (94%), 94 (33%), and 12 (4%) trials, respectively. Assessments of more than one PD biomarker type were reported in 82 studies (29%). Similar proportions of blood-PD (9%), tissue-PD (7%), and imaging-PD studies (8%) had positive results that correlated with clinical activity. Results of 22 PD biomarker studies (8%) were referenced in subsequent clinical trials. CONCLUSIONS: Most phase 1 IO studies performed PD biomarker assessments. Overall, positive PD biomarker results were infrequently correlated with clinical activity or cited in subsequent trials, suggesting a limited impact on subsequent drug development. With emerging health regulatory emphasis on optimal dose selection based on PD activity, more informative and integrative multiplexed assays that capture the complexity of tumour-host immunity interactions are warranted to improve phase 1 IO trial methodology.

Clinical Significance of Radiologically Detected Small Indeterminate Extra-Mammary Lesions in Breast Cancer Patients.

Objective: Patients with breast cancer who have indeterminate extra-mammary lesions, for example in lung, liver or bone, without other metastatic lesions pose a clinical dilemma regarding subsequent management. This study aimed to investigate the prevalence, characteristics and outcomes of such lesions detected on initial staging imaging, and address the clinical significance of these incidental findings. Materials and Methods: Medical records of patients with newly diagnosed breast cancer who underwent computed tomography scans and bone scintigraphy between January 1, 2015 and June 30, 2021 were reviewed. Patients with indeterminate extra-mammary lesions on imaging were included. Patients with obvious metastatic disease were excluded. Lesion characteristics, breast cancer staging, duration of follow-up and natural history of disease progression were analysed. Results: The study included 52 patients with indeterminate lesions on pre-operative imaging. The median follow-up duration was 14 (range: 6-41) months. The most common site of occurrence of indeterminate lesions was the lung (60.9%) followed by the liver (26.1%). Forty-six had lesions that remained stable (88.5%), while six (11.5%) had progression to metastatic disease. Out of these six, only two (3.8%) developed metastasis in the same site as the original indeterminate lesion, whereas the remaining four developed metastases in other sites. Conclusion: Patients with breast malignancy found to have indeterminate extra-mammary lesions without obvious distant metastasis on initial staging scans are associated with a small risk of subsequently developing metastatic disease. Although most of these lesions remain quiescent, surveillance imaging is recommended because a small but significant proportion of patients with such lesions eventually harbour actual metastatic disease.

Suertides A-C: selective antibacterial cyclic hexapeptides from Amycolatopsis sp. MST-135876v3.

Amycolatopsis sp. MST-135876 was isolated from soil collected from the riverbank of El Pont de Suert, Catalonia, Spain. Cultivation of MST-135876 on a range of media led to the discovery of a previously unreported dichlorinated cyclic hexapeptide, suertide A (D-Ser, 5-Cl-D-Trp, 6-Cl-D-Trp, L-Ile, D-Val, D-Glu), featuring an unprecedented pair of adjacent 5/6-chlorotryptophan residues. Supplementing the growth medium with KBr resulted in production of the mono- and dibrominated analogues suertides B and C, respectively. Suertides A-C displayed selective activity against Bacillus subtilis (MIC 1.6 µg ml-1) and Staphylococcus aureus (MIC 3.1, 6.3, and 12.5 µg ml-1, respectively), while suertides A and B showed appreciable activity against methicillin-resistant S. aureus (MIC 1.6 and 6.3 µg ml-1, respectively).

Trauma, Mental Health Distress, and Infectious Disease Prevention Among Women Recently Released From Incarceration.

Background: U.S. women recently released from incarceration experience significantly higher rates of trauma and exacerbation of mental health conditions, and the period following release has been identified as a window of heightened risk for mental health distress and human immunodeficiency virus (HIV), sexually transmitted infections (STI) and hepatitis C (HCV) transmissions. Despite these vulnerabilities, and an urgent need for supports, optimal engagement strategies remain unclear. WORTH Transitions is a program made up of two evidence-based interventions focused on improving the health of women returning to the community from incarceration with substance use disorders. Combining the two was designed to reduce HIV/STIs/HCV risks and increase overall health treatment engagement using a community health worker led intervention. Methods: We examined associations between trauma, mental health symptomology, and HIV/STI/HCV outcomes among women who engaged in the WORTH Transitions intervention (N = 206) Specifically, bivariate and longitudinal multivariate models were created to examine associations between trauma and mental health distress (defined as depressive and PTSD symptoms), on (1) types of engagement in HIV/STIs/HCV prevention and behavioral health services; and (2) HIV/STIs/HCV risk outcomes. The women who engaged in the intervention were 18 years and older and some were White, Black and other racial or ethnic minority. Results: PTSD symptomology and being a Black or indigenous woman of color was significantly (p = 0.014) associated with individual or group session engagement. Neither trauma nor PTSD symptoms were associated with higher HIV/STIs/HCV risks. Instead, relative to those who did not engage in HIV/STI/HCV risky behaviors, PTSD symptomology (p = 0.040) was associated with more than 3-fold increase in the probability of being lost to follow up (relative risk ratio = 3.722). Conclusion: Given the impact of PTSD-related symptoms on driving both engagement in HIV/STIs/HCV prevention services and intervention attrition among women leaving incarceration, physical and behavioral health interventions must be both overtly trauma- and mental health-informed. As was the case with WORTH Transitions, physical and behavioral health services for this population must include intentional and active support of the forms of treatment participants endorse to ensure maximal engagement.

Discovery of brevijanazines from Aspergillus brevijanus reveals the molecular basis for p-nitrobenzoic acid in fungi.

The brevijanazines are novel p-nitrobenzoylated piperazines isolated from Aspergillus brevijanus. Their structures were elucidated by spectroscopic analysis, X-ray crystallography and total synthesis. Heterologous biosynthesis, precursor feeding and in vitro microsomal assays unveiled the biosynthetic pathway to the brevijanazines, featuring a cytochrome P450 oxygenase that converts p-aminobenzoic acid to p-nitrobenzoic acid.

The Arthropod Associates of 155 North American Cynipid Oak Galls.

The identities of most arthropod associates of cynipid-induced oak galls in the western Palearctic are generally known. However, a comprehensive accounting of associates has been performed for only a small number of the galls induced by the estimated 700 species of cynipid gall wasps in the Nearctic. This gap in knowledge stymies many potential studies of diversity, coevolution, and community ecology, for which oak gall systems are otherwise ideal models. We report rearing records of insects and other arthropods from more than 527,306 individual galls representing 201 different oak gall types collected from 32 oak tree species in North America. Of the 201 gall types collected, 155 produced one or more arthropods. A total of 151,075 arthropods were found in association with these 155 gall types, and of these 61,044 (40.4%) were gall wasps while 90,031 (59.6%) were other arthropods. We identified all arthropods to superfamily, family, or, where possible, to genus. We provide raw numbers and summaries of collections, alongside notes on natural history, ecology, and previously published associations for each taxon. For eight common gall-associated genera (Synergus, Ceroptres, Euceroptres, Ormyrus, Torymus, Eurytoma, Sycophila, and Euderus), we also connect rearing records to gall wasp phylogeny, geography, and ecology -including host tree and gall location (host organ), and their co-occurrence with other insect genera. Though the diversity of gall wasps and the large size of these communities is such that many Nearctic oak gall-associated insects still remain undescribed, this large collection and identification effort should facilitate the testing of new and varied ecological and evolutionary hypotheses in Nearctic oak galls.

Yeppoonic acids A - D: 1,2,4-trisubstituted arene carboxylic acid co-metabolites of conglobatin from an Australian Streptomyces sp.

Streptomyces sp. MST-91080 was isolated from a soil sample collected in Queensland, Australia. From this strain, yeppoonic acids A - D were purified and spectroscopically characterised. The yeppoonic acids are a family of diene enecarboxylic acids on a 1,2,4-trisubstituted benzene scaffold, structurally related to other Streptomyces secondary metabolites MF-EA-705α/ß, NFAT-133 and the lorneic acids. Yeppoonic acids B and C show strong cytotoxicity against the NS-1 mouse myeloma cell line (IC50 2.3 µg ml-1 and 3.8 µg ml-1, respectively) and moderate activity against the DU 145 human prostate cancer cell line (IC50 32.8 µg ml-1 and 49.6 µg ml-1, respectively).