Nucleobase-Coupled Xanthones with Anti-ROS Effects from Marine-Derived Fungus Aspergillus sydowii.

A MS/MS-based molecular networking approach compared to the Global Natural Product Social Molecular Networking library, in association with genomic annotation of natural product biosynthetic gene clusters within a marine-derived fungus, Aspergillus sydowii, identified a suite of xanthone metabolites. Chromatographic techniques applied to the cultured fungus led to the isolation of 11 xanthone-based alkaloids, dubbed sydoxanthones F-M. The structures of these alkaloids were elucidated using extensive spectroscopic data, including electronic circular dichroism and single-crystal X-ray diffraction data for configurational assignments. Among these analogues, sydoxanthones F-K exhibit structure features typical of nucleobase-coupled xanthones, with sydoxanthone H being an N-bonded xanthone dimer. Notably, (±)sydoxanthones F (1a/1b), (±)sydoxanthones H (3b/3a), and (±)sydoxanthones J (5b/5a) are enantiomeric pairs, while sydoxanthones G (2), I (4), and K (6) are stereoisomers of 1, 3, and 5, respectively. Furthermore, (+)sydoxanthone H (3a) demonstrated significant rescue of cell viability in H2O2-injuried SH-SY5Y cells by inhibiting reactive oxygen species production, suggesting its potential for neuroprotection.

Brominated Depsidones with Antibacterial Effects from a Deep-Sea-Derived Fungus Spiromastix sp.

Eleven new brominated depsidones, namely spiromastixones U-Z5 (1-11) along with five known analogues (12-16), were isolated from a deep-sea-derived fungus Spiromastix sp. through the addition of sodium bromide during fermentation. Their structures were elucidated by extensive analysis of the spectroscopic data including high-resolution MS and 1D and 2D NMR data. Compounds 6-10 and 16 exhibited significant inhibition against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) with MIC values ranging from 0.5 to 2.0 µM. Particularly, tribrominated 7 displayed the strongest activity against MRSA and VRE with a MIC of 0.5 and 1.0 µM, respectively, suggesting its potential for further development as a new antibacterial agent.

Mammalian Commensal Streptococci Utilize a Rare Family of Class VI Lanthipeptide Synthetases to Synthesize Miniature Lanthipeptide-type Ribosomal Peptide Natural Products.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are natural products with remarkable chemical and functional diversities. These peptides are often synthesized as signals or antibiotics and frequently associated with quorum sensing (QS) systems. With the increasing number of available genomes, many hitherto unseen RiPP biosynthetic pathways have been mined, providing new resources for novel bioactive compounds. Herein, we investigated the underexplored biosynthetic potential of Streptococci, prevalent bacteria in mammal-microbiomes that include pathogenic, mutualistic, and commensal members. Using the transcription factor-centric genome mining strategy, we discovered a new family of lanthipeptide biosynthetic loci under the control of potential QS. By in vitro studies, we investigated the reaction of one of these lanthipeptide synthetases and found that it installs only one lanthionine moiety onto its short precursor peptide by connecting a conserved TxxC region. Bioinformatics and in vitro studies revealed that these lanthipeptide synthetases (class VI) are novel lanthipeptide synthetases with a truncated lyase, a kinase, and a truncated cyclase domain. Our data provide important insights into the processing and evolution of lanthipeptide synthetase to tailor smaller substrates. The data are important for obtaining a mechanistic understanding of the post-translational biosynthesis machinery of the growing variety of lanthipeptides.

Indoloquinazoline alkaloids suppress angiogenesis and inhibit metastasis of melanoma cells.

Metastasis is the leading cause of cancer-related mortality, targeting angiogenesis emerges as a therapeutic strategy for the treatment of melanoma metastasis. Discovery of new antiangiogenic compounds with specific mechanism of action is still desired. In present study, a bioassay-guidance uncovers the EtOAc extract of a marine-derived fungus Aspergillus clavutus LZD32-24 with significant inhibitory activity against the angiogenesis in Tg (fli1a: EGFP) zebrafish model. Extensive chromatographic fractionation led to the isolation of 48 indoloquinazoline alkaloids, including 21 new analogues namely clavutoines A-U (1-21). Their structures were determined by the spectroscopic data, including the ECD, single crystal X-ray diffraction and quantum chemical calculation for the configurational assignments. Among the bioactive analogues, quinadoline B (QB) showed the most efficacy to suppress the zebrafish vascular outgrowth in zebrafish embryos. QB markedly inhibited the migration, invasion and tube formation with weak cytotoxicity in human umbilical vein endothelial cells (HUVECs). Investigation of the mode of action revealed QB suppressed the ROCK/MYPT1/MLC2/coffin and FAK /Src signaling pathways, and subsequently disrupted actin cytoskeletal organization. In addition, QB reduced the number of new vessels sprouting from the ex vivo chick chorioallantoic membrane (CAM), and inhibited the metastasis of B16F10 melanoma cells in lung of C57BL/6 mice through suppressing angiogenesis. These findings suggest that QB is a potential lead for the development of new antiangiogenic agent to inhibit melanoma metastasis.

Discovery of cyclohexadepsipeptides with anti-Zika virus activities and biosynthesis of the nonproteinogenic building block (3S)-methyl-l-proline.

The fungal cyclohexadepsipeptides destruxins (DTXs), isaridins (ISDs), and isariins (ISRs) are nonribosomal peptides whose structures include a 19-membered ring composed of five amino acid residues and one α- or ß-hydroxy acid residue. These cyclohexadepsipeptides contain unusual nonproteinogenic amino acid-building blocks and possess a range of antiviral, antibacterial, and other activities. The biosynthetic gene clusters for ISDs and ISRs have not been identified, and the biosynthesis of the nonproteinogenic (3S)-methyl-l-proline residue, which is found in DTXs, ISDs, and many other natural products, lacks full characterization. In an ongoing effort to identify compounds that can inhibit the Zika virus (ZIKV), we examined the extract of marine-derived fungus Beauveria felina SX-6-22 and discovered 30 DTXs, ISDs, and ISRs (1-30) including seven new compounds (1-7). The anti-ZIKV assays showed that 9-12 and 16-18 possess inhibitory activities against ZIKV RNA replication and NS5 (nonstructural protein 5) production in ZIKV-infected A549 cells. We sequenced the genome of B. felina SX-6-22 and identified three biosynthetic gene clusters detx, isd and isr, which are responsible for the biosynthesis of DTXs, ISDs, and ISRs, respectively. Comparative analyses of the three gene clusters clarified the biosynthetic relationships among these cyclohexadepsipeptides. Finally, we characterized the entire biosynthesis of nonproteinogenic building block (3S)-methyl-l-proline. The Δ1-pyrroline-5-carboxylate reductases (P5CRs), also used in the biosynthesis of l-proline, were demonstrated to catalyze the final reduction step in (3S)-methyl-l-proline formation, suggesting potential cross talk between primary and secondary metabolisms. These results provide opportunities for biosynthetic pathway engineering to generate new anti-ZIKV cyclohexadepsipeptides.

Sclerotiamides C-H, Notoamides from a Marine Gorgonian-Derived Fungus with Cytotoxic Activities.

Bioassay-guided fractionation in association with LC-MS and NMR detection led to the isolation of six new alkaloids, sclerotiamides C-H (1-6), from the marine gorgonian-derived fungus Aspergillus sclerotiorum LZDX-33-4. Their structures were determined from extensive spectroscopic data, including ECD data and single-crystal X-ray diffraction analysis for configurational assignments. Sclerotiamides C (1) and D (2) are notoamide-type alkaloids with the incorporation of a unique 2,2-diaminopropane unit, and sclerotiamides E (3) and F (4) are unprecedented notoamide hybrids with a new coumarin unit. Sclerotiamide H (6) represents a new highly oxidized notoamide scaffold. Sclerotiamides C and F showed significant inhibition against a panel of tumor cell lines with IC50 values ranging from 1.6 to 7.9 µM. Sclerotiamide C induces apoptosis in HeLa cells by arresting the cell cycle, activating ROS production, and regulating apoptosis-related proteins in the MAPK signaling pathway. The present study extends the scaffold diversity of the notoamides and provides a potential lead for the development of a cytotoxic agent.

Concise Biosynthesis of Tropone-Containing Spiromaterpenes by a Sesquiterpene Cyclase and a Multifunctional P450 from a Deep-Sea-Derived Spiromastix sp. Fungus.

Spiromaterpenes are a group of rare tropone-containing sesquiterpenes with antineuroinflammatory activity. Herein, we elucidate their biosynthetic pathway in a deep-sea-derived Spiromastix sp. fungus by heterologous expression, biochemical characterization, and incubation experiments. The sesquiterpene cyclase SptA was first characterized to catalyze the production of guaia-1(5),6-diene, and a multifunctional cytochrome P450 catalyzed the tropone ring formation. These results provide important clues for the rational mining of bioactive guaiane-type sesquiterpenes and expand the repertoire of P450 activities to synthesize unique building blocks of natural products.

Versicotide G suppresses osteoclastogenesis and prevents osteolysis.

Excessive formation and function of osteoclasts cause various osteolytic bone diseases. Natural products are a potential source for the discovery of new therapeutic candidates to treat bone destruction diseases. In this study, chemical informatics and bioassay guided examination of the marine-derived Aspergillus versicolor F77 fungus chemically resulted in the isolation of seven cyclopeptides, of which versicotides G-J (1-4) are new cyclohexapeptides. Their structures were identified by spectroscopic data in association with Marfey method and single crystal X-ray diffraction data for configurational assignments. Bioassay revealed that versicotide G (1, VG) is the most active among the analogs to suppress the receptor activator of nuclear factor-KB ligand (RANKL)-induced osteoclastogenesis in bone marrow derived monocytes (BMMs) without affecting BMMs viability. VG also suppressed RANKL-induced actin-ring formation and resorbing function of osteoclast dose-dependently. Mechanistically, VG attenuated RANKL-induced intracellular calcium elevation by inhibiting PLCγ1 phosphorylation and blocking the activation of downstream phosphatase calcineurin. In addition, VG abrogated the expression and translocation of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), leading to the downregulation of the expression of osteoclast-specific genes and the abolishment of the osteoclast formation. In the in vivo test, VG suppressed osteoclast formation and bone loss in Ti-induced calvarial osteolytic mouse model.These findings imply that VG is a promising candidate for the remedy of bone destruction-related diseases.

Eremophilane-Type Sesquiterpenes from a Marine-Derived Fungus Penicillium Copticola with Antitumor and Neuroprotective Activities.

Chemical examination of a marine sponge-associated Penicillium copticola fungus resulted in the isolation of ten undescribed eremophilanes, namely copteremophilanes A-J (1-10), along with two new glycosides, 5-glycopenostatin F (11) and 5-glucopenostatin I (12). Their structures were determined by extensive spectroscopic data, in association with ECD data and chemical conversions for configurational assignments. Analogs 1, 2, and 10 represent a group of uncommon skeletons of eremophilanes with an aromatic ring and a methyl migration from C-5 to C-9, and analogs 11 and 12 are characteristic of a PKS scaffold bearing a glucose unit. The incorporation of a chlorinated phenylacetic unit in 3-9 is rarely found in nature. Analog 7 showed neuroprotective effect, whereas 8 exhibited selective inhibition against human non-small cell lung cancer cells (A549). This study enriched the chemical diversity of eremophilanes and extended their bioactivities to neuroprotection.

Rapid colonization and biodegradation of untreated commercial polyethylene wrap by a new strain of Bacillus velezensis C5.

Biodegradation could be a potential alternative solution to polyethylene (PE) pollution. However, its hydrophobic surface and long carbon chains make extremely low biodegradation efficiency. In this study, we screened a novel potential bacterial strain C5 (CGMCC number: 1.18715) for low-density polyethylene (LDPE) biodegrading from landfills. The strain was identified as Bacillus velezensis according to its 16S rRNA sequence. The contact angle analysis indicated that C5 could rapidly form biofilm on untreated LDPE which resulted in contact angles decreasing from 100° to 54° over 7 d. After the LDPE film incubated with C5 for 90 d, the thickness and weight of LDPE film decreased by 26% and 8.01%, respectively. Besides, the biotreated PE film was found with increases in weight-averaged molecular weight by 29.8%, suggesting low molar mass chains were consumed. C24-C29 n-alkanes were detected in the biodegradation products, which proved the depolymerization of LDPE. Combined with the genome mining results, a possible biofilm-aided degrading mechanism was proposed and might involve key enzymes, such as laccase, cytochrome P450 and propionyl-CoA carboxylase, which could constitute a multienzyme system for the co-catalytic degradation of LDPE waste.

Epigenetic Manipulation to Trigger Production of Guaiane-Type Sesquiterpenes from a Marine-Derived Spiromastix sp. Fungus with Antineuroinflammatory Effects.

Epigenetic manipulation of a deep-sea sediment-derived Spiromastix sp. fungus using suberoylanilide hydroxamic acid (SAHA) induction resulted in the activation of a terpene-related biosynthetic gene cluster, and nine new guaiane-type sesquiterpenes, spiromaterpenes A-I (1-9), were isolated. Their structures were determined using various spectroscopic techniques, in association with the modified Mosher's method, computed electronic circular dichroism (ECD) spectra, and chemical conversion for configurational assignments. Compounds 4-6 exhibited significant effects against the NO production on lipopolysaccharide (LPS)-induced microglia cells BV2, and the preliminary SAR analyses demonstrated that a 2(R),11-diol unit is favorable. The most active 5 abolished LPS-induced NF-κB translocation from the cytosol to the nucleus in BV-2 microglial cells, accompanied by the marked reduction of the transcription levels of pro-inflammatory cytokines, including IL-1ß, IL-6, and TNF-α dose-dependently in both LPS-induced BV-2 and BV-2 cells, as well as the protein and mRNA levels of iNOS and COX-2. This study complements the gap in knowledge regarding the anti-neuroinflammatory activity of guaiane-type sesquiterpenoids at the cellular level and suggests that 5 is promising for further optimization as a multifunctional agent for antineuroinflammation.

Enhanced resistance of Trichoderma harzianum LZDX-32-08 to hygromycin B induced by sea salt.

OBJECTIVES: To determine the effect of sea salt on the resistance of Trichoderma harzianum LZDX-32-08 to hygromycin B and speculate the possible mechanisms involved via transcriptome analysis. RESULTS: Sea salt addition in media to simulate marine environment significantly increased the tolerance of marine-derived fungus Trichoderma harzianum LZDX-32-08 to hygromycin B from 40 to 500 µg/ml. Meanwhile, sea salt addition also elicited the hygromycin B resistance of 5 other marine or terrestrial fungi. Transcriptomic analyses of T. harzianum cultivated on PDA, PDA supplemented with sea salt and PDA with both sea salt and hygromycin B revealed that genes coding for P-type ATPases, multidrug resistance related transporters and acetyltransferases were up-regulated, while genes coding for Ca2+/H+ antiporter and 1,3-glucosidase were down-regulated, indicating probable increased efflux and inactivation of hygromycin B as well as enhanced biofilm formation, which could jointly contribute to the drug resistance. CONCLUSIONS: Marine environment or high ion concentration in the environment could be an importance inducer for antifungal resistance. Possible mechanisms and related key genes were proposed for understanding the molecular basis and overcoming this resistance.

Enhancing robustness of activated sludge with Aspergillus tubingensis as a protective backbone structure under high-salinity stress.

High salt seriously destroys the stable interactions among key functional species of activated sludge, which in turn limits the performance of high-salinity wastewater biological treatment. In this study, pelletized Aspergillus tubingensis (AT) was used as a protective backbone structure for activated sludge under high-salinity stress, and a superior salt-tolerant AT-based aerobic granular sludge (AT-AGS) was developed. Results showed that the COD and NH4+-N removal efficiencies of salt-domesticated AT-AGS were 11.83% and 7.18% higher than those of salt-domesticated flocculent activated sludge (FAS) at 50 gNaCl/L salinity. Compared to the salt-domesticated FAS, salt-domesticated AT-AGS showed stronger biomass retention capacity (with a MLVSS concentration of 7.92 g/L) and higher metabolic activity (with a dehydrogenase activity of 48.06 mgTF/gVSS·h). AT modified the extracellular polymeric substances pattern of microbes, and the total extracellular polysaccharide content of AT-AGS (80.7 mg/gVSS) was nearly twice than that of FAS (46.3 mg/gVSS) after salt-domestication, which demonstrated that extracellular polysaccharide played a key role in keeping the system stable. The high-throughput sequencing analysis illustrated that AT contributed to maintain the microbial richness and diversity of AT-AGS in high-salt environment, and Marinobacterium (with a relative abundance of 32.04%) became the most predominant genus in salt-tolerant AT-AGS. This study provided a novel insight into enhancing the robustness of activated sludge under high-salinity stress.

Reinvestigation of the substrate specificity of a reverse prenyltransferase NotF from Aspergillus sp. MF297-2.

NotF from Aspergillus sp. MF297-2 and BrePT from Aspergillus versicolor catalyze a reverse C2-prenylation of brevianamide F in the biosynthetic pathway of brevianamides and notoamides. NotF was reported to use only brevianamide F as substrate while BrePT demonstrated broad substrate promiscuity. With high identity at amino acid level, it is interesting to reinvestigate the catalytic activities of these two prenyltransferases in vitro toward 14 cyclodipeptides. Product identification of the in vitro assays by MS proved that NotF and BrePT share similar catalytic ability and substrate promiscuity.

New perspectives on the treatment of mycobacterial infections using antibiotics.

More than 100 years have passed since the discovery of Mycobacterium tuberculosis, in 1882, as the pathogen that causes tuberculosis (TB). However, globally, TB is still one of the leading causes of death by infectious diseases. In 2018, approximately 10.0 million people were diagnosed with TB owing to the development of advanced strategies by M. tuberculosis to resist antibiotics, including the development of a dormant state. The World Health Organization (WHO) and the Sustainable Development Goals (SDGs) are dedicated to ending TB by 2030. However, the development of strategies to discover new TB drugs and new therapies is crucial for the achievement of this goal. Unfortunately, the rapid occurrence of multidrug-resistant strains of M. tuberculosis has worsened the current situation, thereby warranting prioritized discovery of new anti-TB drugs and the development of new treatment regimens in academia and the pharmaceutical industry. In this mini review, we provide a brief overview of the current research and development pipeline for new anti-TB drugs and present our perspective of TB drug innovation. The data presented herein may enable the introduction of more effective medicines and therapeutic regimens into the market.Key Points• The Updated Global New TB Drug Pipelines are briefly summarized.• Novel strategies for the discovery of new TB drugs, including novel sources, bioinformatics, and synthetic biology strategies, are discussed.• New therapeutic options, including living therapeutics and phage therapy, are proposed.

High-strength anaerobic digestion wastewater treatment by aerobic granular sludge in a step-by-step strategy.

To reduce the instability of aerobic granular sludge (AGS) caused by high-strength anaerobic digestion wastewater, a strategy of increasing proportion of anaerobic digestion wastewater step-by-step was adopted in this study. High-performance stable AGSs were successfully cultivated with sequencing batch reactors by this strategy, which could efficiently treat high-strength anaerobic digestion wastewater with an influent chemical oxygen demand (COD) up to 5090 mg⋅L-1. After six phases of stepwise increasing COD loads, the sludge sizes increased from 0.5 mm to 1.5 mm, with the final mixed liquor suspended solids increased to 13,814 mg⋅L-1, and the final sludge volume index decreased to 15 mL⋅g-1. The extracellular polymeric substance (EPS), which is crucial to keep the stability of AGS, increased continuously from 85.1 mg⋅g-1 SS to 307.8 mg⋅g-1 SS with the increase of COD loads. Moreover, the removal efficiency of COD and TN could reach 92% and 87% for real high-strength anaerobic digestion wastewater treatment. The bacterial community analysis revealed that the family Rhodocyclaceae, Flavobacteriaceae, and Xanthomonadaceae were the major microbes of AGS, and were responsible for COD and TN removal, as well as EPS secretion. These findings may provide novel information and enrich AGS treatment of high-strength real wastewater.

Enhancing robustness of aerobic granule sludge under low C/N ratios with addition of kitchen wastewater.

Aerobic granular sludge (AGS) is one of the most promising biotechnologies for wastewater treatment. However, the instability of AGS at low carbon to nitrogen (C/N) ratios limited its application. In this study, kitchen wastewater addition in the influent was found to improve the morphology, characteristics, and treatment performance of AGS at low C/N ratios of 10, 5 and 2, which strongly reduced the negative impact of low C/N ratios on the biomass concentration, settleability, EPS secretion, stability and performance of AGS. At C/N ratio of 2, sludge disintegration was observed in RA with synthetic wastewater as influent, while the sludge in RB was able to keep a compact microbial structure with particle size of 1.0-1.5 mm. When C/N ratio decreased from 20 to 2 (phase 1 to 4), the MLSS, SVI and EPS secretion in RB were negatively affected at the beginning of each phase, but recovered to 4800 mg L-1, 60 mL g-1, and 86 mg/g SS at the end of phase 4 (C/N ratio of 2), which were 1.3, 0.6 and 1.3 times of those in RA, respectively. Meanwhile, the removal efficiencies of COD, TN, TP and NH4+-N in RB were 90%, 73%, 53%, and 99% at the end of phase 4, which were 1.1, 1.2, 2.2 and 2.4 times of those in RA, respectively. Thus, high-performance AGS with enhanced robustness and high abundance of HN-AD functional bacteria Paracoccus was obtained. These findings provided a promising and cost-effective method to improve the long-term stability and performance of AGS dealing with wastewater of low C/N ratio.

A cryptic pigment biosynthetic pathway uncovered by heterologous expression is essential for conidial development in Pestalotiopsis fici.

Spore pigmentation is very common in the fungal kingdom. The best studied pigment in fungi is melanin which coats the surface of single cell spores. What and how pigments function in a fungal species with multiple cell conidia is poorly understood. Here, we identified and deleted a polyketide synthase (PKS) gene PfmaE and showed that it is essential for multicellular conidial pigmentation and development in a plant endophytic fungus, Pestalotiopsis fici. To further characterize the melanin pathway, we utilized an advanced Aspergillus nidulans heterologous system for the expression of the PKS PfmaE and the Pfma gene cluster. By structural elucidation of the pathway metabolite scytalone in A. nidulans, we provided chemical evidence that the Pfma cluster synthesizes DHN melanin. Combining genetic deletion and combinatorial gene expression of Pfma cluster genes, we determined that the putative reductase PfmaG and the PKS are sufficient for the synthesis of scytalone. Feeding scytalone back to the P. fici ΔPfmaE mutant restored pigmentation and multicellular adherence of the conidia. These results cement a growing understanding that pigments are essential not simply for protection of spores from biotic and abiotic stresses but also for spore structural development.

Switching a regular tryptophan C4-prenyltransferase to a reverse tryptophan-containing cyclic dipeptide C3-prenyltransferase by sequential site-directed mutagenesis.

FgaPT2 from Aspergillus fumigatus catalyzes a regular C4- and its mutant K174A a reverse C3-prenylation of l-tryptophan in the presence of dimethylallyl diphosphate. FgaPT2 also uses tryptophan-containing cyclic dipeptides for C4-prenylation, while FgaPT2_K174A showed almost no activity toward these substrates. In contrast, Arg244 mutants of FgaPT2 accept very well cyclic dipeptides for regular C4-prenylation. In this study, we demonstrate that FgaPT2_K174F, which catalyzes a regular C3-prenylation on tyrosine, can also use cyclo-l-Trp-l-Ala, cyclo-l-Trp-l-Trp, cyclo-l-Trp-Gly, cyclo-l-Trp-l-Phe, cyclo-l-Trp-l-Pro, and cyclo-l-Trp-l-Tyr as substrates, but only with low activity. Combinational mutation on Lys174 and Arg244 increases significantly the acceptance of these cyclic dipeptides. With the exception of cyclo-l-Trp-l-Trp, the tested dipeptides were much better accepted by FgaPT2_K174F_R244X (X = L, N, Q, Y) than FgaPT2, with an increase of two- to six-fold activity. In comparison to FgaPT2_K174F, even two- to ten-fold conversion yields were calculated for the double mutants. Isolation and structural elucidation of the enzyme products revealed stereospecific reverse C3-prenylation on the indole ring, resulting in the formation of syn-cis configured hexahydropyrroloindole derivatives. The results presented in this study highlight the convenience of site-directed mutagenesis for creating new biocatalysts.

Mutation on Gly115 and Tyr205 of the cyclic dipeptide C2-prenyltransferase FtmPT1 increases its catalytic activity toward hydroxynaphthalenes.

The fungal cyclic dipeptide prenyltransferase FtmPT1 from Aspergillus fumigatus catalyzes a regular C2-prenylation of brevianamide F (cyclo-L-Trp-L-Pro) and is involved in the biosynthesis of a number of biologically active natural products including tryprostatins, spirotryprostatins, verruculogen, and fumitremorgins. FtmPT1, like other members of the dimethylallyltryptophan synthase superfamily, was shown to have high substrate promiscuity for tryptophan-containing cyclic dipeptides and a few other aromatic substrates. A previous study demonstrated the acceptance of 1-naphthol by FtmPT1, but with very low product yield. In this study, we report the significantly increased acceptance of 1-naphthol and other hydroxynaphthalenes by FtmPT1_G115A and six FtmPT1_Y205X single mutants as well as FtmPT1_G115A_Y205C. These results provided an example for creation of biocatalysts with improved catalytic activity by site-directed mutagenesis.