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Background: Phytopathogenic bacteria cause severe losses to crops every year. The management of crop bacterial diseases with chemical agents has been considered as the main strategy. In order to cope with the bactericide resistance made by the pathogens, new antibacterials need to be continuously developed., Results: A chemical investigation from the endophytic fungus Rhexocercosporidium sp. Dzf14 has led to the isolation of 12 diphenyl ethers including two new ones named rhexocerin E (1) and rhexocercosporin G (2), along with two new depsides named rhexocerdepsides A (3) and B (4). The structures and absolute configurations of the new compounds were determined through comprehensive analysis of spectroscopic data and quantum chemical ECD calculations. Diphenyl ethers showed obviously antibacterial activity on Gram-positive bacteria. The structure-activity relationship of diphenyl ethers revealed that prenylation was critical to the antibacterial activity. Among them, rhexocercosporin D (12) possessed the strongest activity against Clavibacter michiganensis and Bacillus subtilis, and was selected for further mechanistic studies. It was found that rhexocercosporin D displayed bactericidal activity by affecting homeostasis of cell membranes. In addition to its rapid bactericidal effects on Gram-positive bacteria, rhexocercosporin D could restore the susceptibility against Gram-negative Agrobacterium tumefaciens by synergistic action with colistin., Conclusion: Twelve diphenyl ethers and two depsides were isolated from endophytic fungus Rhexocercosporidium sp. Dzf14. Isopentenyl was critical for diphenyl ethers against Gram-positive bacteria. Rhexocercosporin D could affect homeostasis of bacterial cell membrane to exert rapid bactericidal activity. These findings highlight the antibacterial potential of the diphenyl ethers in crop bacterial disease management. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

A known monoterpene, named γ-terpineol, was incorporated in mixed Langmuir monolayers composed of dipalmitoyl-phosphoethanolamine (DPPE) and peptidoglycans as a model of microbial membranes. Surface pressure and surface potential isotherms, dynamical surface rheology, Brewster angle microscopy (BAM), and infrared spectroscopy were employed to characterize the compound-membrane interactions. The compound expanded the monolayers denoting repulsive interactions. At 30 mN/m, the monolayer presented lower viscoelastic and in-plane elasticity parameters and an increased all-trans/gauche conformers ratio for the alkyl chains, confirming molecular order. The morphology of the monolayer was analyzed by BAM, which revealed a heterogeneous distribution of γ-terpineol along the mixed monolayer, which tends to segregate. In conclusion, the compound changes the thermodynamic, electric, rheological, morphological, and structural properties of the peptidoglycan-DPPE monolayer, which may be essential to understand, at the molecular level, the action of bioactives in selected membrane models., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The research on bioactive secondary metabolites from Aspergillus fumigatus afforded six compounds, which were identified by mass spectrometer (MS) and nuclear magnetic resonance (NMR) spectroscopic analysis as cyclopyazonic acid (1), trypacidin A (2), asterric acid (3), methyl asterrate (4), demethylcitreoviranol (5), as well as (5-hydroxy-2-oxo-2H-pyran-4-yl) methyl acetate (6). Cyclopyazonic acid (1) was found to have potent antibacterial effects, especially against Bacillus licheniformis with minimal inhibitory concentration (MIC) value of 3.7μg/mL. Its antibacterial effects were possibly related to the olefinic acid group in the structure. Phenyl ether derivatives 3 and 4, and trypacidin A (2) also exhibited antimicrobial effects. In addition, compound 6 showed significant antioxidant effects with half maximal effective concentration (EC 50 ) value of 10.2μM in the ABTS (2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid) assay, which was better than the positive control.

The extract of the strain Aspergillus flavipes DL-11 exerted antibacterial activities against six Gram-positive bacteria. During the following bioassay-guided separation, ten diphenyl ethers (1-10), two benzophenones (11-12), together with two xanthones (13-14) were isolated. Among them, 4'-chloroasterric acid (1) was a new chlorinated diphenyl ether. Their structures were elucidated by extensive spectroscopic data analysis, including IR, HR-ESI-MS, NMR experiments, and by comparison with the literature data. All compounds showed moderate to strong antibacterial effects on different Gram-positive bacteria with MIC values that ranged from 3.13 to 50 μg/mL, but none of the compounds exhibited activity against Gram-negative bacteria Vibrio parahaemolyticus ATCC17802 (MIC>100 μg/mL). In particular, the MICs of some compounds are at the level of positive control., (© 2019 Wiley-VHCA AG, Zurich, Switzerland.)

Diphenyl ethers (DPE) and its analogs have exhibited excellent potential for therapeutic and industrial applications. Since the 19th century, intensive research is perpetuating on the synthetic routes and biological properties of DPEs. Few well-known DPEs are Nimesulide, Fenclofenac, Triclosan, Sorafenib, MK-4965, and MK-1439 which have shown the potential of this moiety as a lead scaffold for different pharmacological properties. In this review, we recapitulate the diverse synthetic route of DPE moiety inclusive of merits and demerits over the classical synthetic route and how this moiety sparked an interest in researchers to discern the SAR (Structure Activity Relationship) for the development of diversified biological properties of DPEs such as antimicrobial, antifungal, antiinflammatory & antiviral activities., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A chemical-epigenetic method was used to enhance the chemodiversity of a marine algicolous fungus. Apart from thirteen known compounds, (+)-brevianamide R ((+)- 3 ), (‒)-brevianamide R ((‒)- 3 ), (+)-brevianamide Q ((+)- 4 ), (‒)-brevianamide Q ((‒)- 4 ), brevianamide V ((+)- 5 ), brevianamide W ((‒)- 5 ), brevianamide K ( 6 ), diorcinol B ( 7 ), diorcinol C ( 8 ), diorcinol E ( 9 ), diorcinol J ( 10 ), diorcinol ( 11 ), 4-methoxycarbonyldiorcinol ( 12 ), two new compounds, (+)- and (‒)-brevianamide X ((+)- and (‒)- 2 )), as well as a new naturally occurring one, 3-[6-(2-methylpropyl)-2-oxo-1 H -pyrazin-3-yl]propanamide ( 1 ), were isolated from chemical-epigenetic cultures of Aspergillus versicolor OUCMDZ-2738 with 10 µM vorinostat (SAHA). Compared to cultures in the same medium without SAHA, compounds 1 ⁻ 4 , 8 , 9 , 11 , and 12 were solely observed under SAHA condition. The structures of these compounds were elucidated based on spectroscopic analysis, specific rotation analysis, ECD, and X-ray crystallographic analysis. (±)- 3 , (±)- 4 , and (±)- 5 were further resolved into the corresponding optically pure enantiomers and their absolute configurations were determined for the first time. Compounds 11 and 12 showed selective antibacterial against Pseudomonas aeruginosa with a minimum inhibitory concentration (MIC) of 17.4 and 13.9 μM, respectively. Compound 10 exhibited better α-glucosidase inhibitory activity than the assay control acarbose with IC 50 values of 117.3 and 255.3 μM, respectively.

One new diphenyl ether, diorcinol K (1), along with three known compounds, diorcinols D (2), F (3) and I (4) were isolated from the fermentation media of a marine-derived fungus Aspergillus sp. CUGB-F046 which was isolated from a sediment sample collected from the Bohai Sea, China. Their structures were elucidated by detailed spectroscopic methods. Compounds 1, 2 and 4 displayed significant antibacterial activities against Staphylococcus aureus and methicillin-resistant S. aureus with MIC values of 3.125, 6.25 and 6.25 μg/mL, respectively.

Chloropupukeananin and chloropestolides are novel metabolites of the plant endophyte Pestalotiopsis fici, showing antimicrobial, antitumor, and anti-HIV activities. Their highly complex and unique skeletons were generated from the coisolated pestheic acid (1) and iso-A82775C (10) based on our previous studies. Here, we identified the biosynthetic gene cluster iac of 10 and characterized an iacE encoded prenyltransferase. Deletion of iacE abolished iso-A82775C production, accumulated the prenyl group-lacking siccayne (2), and generated four new chloropestolides (3-6). Compounds 5 and 6 showed antibacterial effects against Staphylococcus aureus and Bacillus subtilis, and 5 was also cytotoxic to human tumor cell lines HeLa, MCF-7, and SW480. These results provided the first genetic and biochemical insights into the biosynthesis of natural prenylepoxycyclohexanes and demonstrated the feasibility for generation of diversified congeners by manipulating the biosynthetic genes of 10.

Self-immolative polymers (SIMPs) are macromolecules that spontaneously undergo depolymerization into small molecules when triggered by specific external stimuli. We report here the first examples of antimicrobial SIMPs with potent, rapid, and broad-spectrum bactericidal activity. Their antibacterial and hemolytic activities were examined as a function of cationic functionality. Polymers bearing primary ammonium cationic groups showed more potent bactericidal activity against Escherichia coli, relative to tertiary and quaternary ammonium counterparts, whereas the quaternary ammonium polymers showed the lowest hemolytic toxicity. These antibacterial polycations undergo end-to-end depolymerization when triggered by an externally applied stimulus. Specifically, poly(benzyl ether)s end-capped with a silyl ether group and bearing pendant allyl side chains were converted to polycations by photoinitiated thiol-ene radical addition using cysteamine HCl. The intact polycations are stable in solution, but they spontaneously unzip into their component monomers upon exposure to fluoride ions, with excellent sensitivity and selectivity. Upon triggered depolymerization, the antibacterial potency was largely retained but the hemolytic toxicity was substantially reduced. Thus, we reveal the first example of a self-immolative antibacterial polymer platform that will enable antibacterial materials to spontaneously unzip into biologically active small molecules upon the introduction of a specifically designed stimulus.

Three new diphenyl ether derivatives-phomaethers A-C ( 1 - 3 ) and five known compounds-including a diphenyl ether analog, 2,3'-dihydroxy-4-methoxy-5',6-dimethyl diphenyl ether ( 4 ); and four isocoumarin derivatives, diaportinol ( 5 ), desmethyldiaportinol ( 6 ), citreoisocoumarinol ( 7 ), and citreoisocoumarin ( 8 )-were isolated from a gorgonian-derived fungus Phoma sp. (TA07-1). Their structures were elucidated by extensive spectroscopic investigation. The absolute configurations of 1 and 2 were determined by acid hydrolysis reactions. It was the first report to discover the diphenyl glycoside derivatives from coral-derived fungi. Compounds 1 , 3 , and 4 showed selective strong antibacterial activity against five pathogenic bacteria with the minimum inhibiting concentration (MIC) values and minimum bactericidal concentration (MBC) values between 0.156 and 10.0 μM., Competing Interests: The authors declare no conflict of interest.

There is growing awareness of the link between drug-target residence time and in vivo drug activity, and there are increasing efforts to determine the molecular factors that control the lifetime of a drug-target complex. Rational alterations in the drug-target residence time require knowledge of both the ground and transition states on the inhibition reaction coordinate, and we have determined the structure-kinetic relationship for 22 ethyl- or hexyl-substituted diphenyl ethers that are slow-binding inhibitors of bpFabI1, the enoyl-ACP reductase FabI1 from Burkholderia pseudomallei. Analysis of enzyme inhibition using a two-dimensional kinetic map demonstrates that the ethyl and hexyl diphenyl ethers fall into two distinct clusters. Modifications to the ethyl diphenyl ether B ring result in changes to both on and off rates, where residence times of up to ∼700 min (∼11 h) are achieved by either ground state stabilization (PT444) or transition state destabilization (slower on rate) (PT404). By contrast, modifications to the hexyl diphenyl ether B ring result in residence times of 300 min (∼5 h) through changes in only ground state stabilization (PT119). Structural analysis of nine enzyme:inhibitor complexes reveals that the variation in structure-kinetic relationships can be rationalized by structural rearrangements of bpFabI1 and subtle changes to the orientation of the inhibitor in the binding pocket. Finally, we demonstrate that three compounds with residence times on bpFabI1 from 118 min (∼2 h) to 670 min (∼11 h) have in vivo efficacy in an acute B. pseudomallei murine infection model using the virulent B. pseudomallei strain Bp400.

A series of 4,4'-bis-[2-(6-N-substituted-amidino)indolyl] diphenyl ether have been synthesized and tested for their in vitro antibacterial activity including a range of Gram-positive and Gram-negative pathogens and cytotoxicity. Most of these compounds have mainly shown anti-Gram positive bacteria activities especially against drug resistant bacterial strains MRSA, MRSE and VRE. The anti-MRSA and anti-MRSE activities of compound 7a and 7j were more potent than that of the lead compound 2, levofloxacin and vancomycin. Interestingly, 7j had greatly improved anti negative bacterial activity, especially for the producing NDM-1 Klebsiella pneumonia strain and less toxic than that of the lead compound 2., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We describe the synthesis and biological evaluation of riccardin D derivatives, a novel class of antimicrobial molecules. Structural diversification of these derivatives was achieved by introducing hydroxy, methoxy, and bromine into the aromatic rings of riccardin D. The antimicrobial evaluation of these compounds was performed as in vitro assays against clinically isolated bacteria and fungi. The introduction of bromine atom into the arene B of riccardin D led to several strongly active antibacterial compounds with a MIC value ranging from 0.5 to 4μg/mL for Staphylococcus aureus, both methicillin-sensitive and -resistant strains. Antifungal tests found compound 34 was the most potent molecule with a MIC value of 2μg/mL against Candida albicans. This initial biological evaluation suggests that these novel molecules merit further investigation as potential antimicrobial agents., (Copyright © 2016. Published by Elsevier Ltd.)

Most existing antibiotics were discovered through screens of environmental microbes, particularly the streptomycetes, for the capacity to prevent the growth of pathogenic bacteria. This "activity-guided screening" method has been largely abandoned because it repeatedly rediscovers those compounds that are highly expressed during laboratory culture. Most of these metabolites have already been biochemically characterized. However, the sequencing of streptomycete genomes has revealed a large number of "cryptic" secondary metabolic genes that are either poorly expressed in the laboratory or that have biological activities that cannot be discovered through standard activity-guided screens. Methods that reveal these uncharacterized compounds, particularly methods that are not biased in favor of the highly expressed metabolites, would provide direct access to a large number of potentially useful biologically active small molecules. To address this need, we have devised a discovery method in which a chemical elicitor called Cl-ARC is used to elevate the expression of cryptic biosynthetic genes. We show that the resulting change in product yield permits the direct discovery of secondary metabolites without requiring knowledge of their biological activity. We used this approach to identify three rare secondary metabolites and find that two of them target eukaryotic cells and not bacterial cells. In parallel, we report the first paired use of cheminformatic inference and chemical genetic epistasis in yeast to identify the target. In this way, we demonstrate that oxohygrolidin, one of the eukaryote-active compounds we identified through activity-independent screening, targets the V1 ATPase in yeast and human cells and secondarily HSP90.

PT70 is a diaryl ether inhibitor of InhA, the enoyl-ACP reductase in the Mycobacterium tuberculosis fatty acid biosynthesis pathway. It has a residence time of 24 min on the target, and also shows antibacterial activity in a mouse model of tuberculosis infection. Due to the interest in studying target tissue pharmacokinetics of PT70, we developed a method to radiolabel PT70 with carbon-11 and have studied its pharmacokinetics in mice and baboons using positron emission tomography., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Eleven new polyphenols namely spiromastols A-K (1-11) were isolated from the fermentation broth of a deep sea-derived fungus Spiromastix sp. MCCC 3A00308. Their structures were determined by extensive NMR data and mass spectroscopic analysis in association with chemical conversion. The structures are classified as diphenyl ethers, diphenyl esters and isocoumarin derivatives, while the n-propyl group in the analogues is rarely found in natural products. Compounds 1-3 exhibited potent inhibitory effects against a panel of bacterial strains, including Xanthomanes vesicatoria, Pseudomonas lachrymans, Agrobacterium tumefaciens, Ralstonia solanacearum, Bacillus thuringensis, Staphylococcus aureus and Bacillus subtilis, with minimal inhibitory concentration (MIC) values ranging from 0.25 to 4 µg/mL. The structure-activity relationships are discussed, while the polychlorinated analogues 1-3 are assumed to be a promising structural model for further development as antibacterial agents.

A new family of poly-guanidinium species with a benzene core as the organising agent has been developed. Their antibacterial properties have been evaluated against reference Gram positive and Gram negative bacteria, and their cytotoxicity against eukaryotic cells. Most of these compounds exhibited Minimum Inhibitory Concentrations in the micromolar range., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A new Schiff base ligand was synthesized by reaction of salicylaldehyde with 1,6-bis(4-chloro-2-aminophenoxy)hexane. Then the Schiff base complexes were synthesized by metal salts and the Schiff base. The metal to ligand ratio of metal complexes was found to be 1:1. The Cu(II) complex is proposed to be square planar and the Co(II), Ni(II), Mn(II) and Zn(II) complexes are proposed to be tetrahedral geometry. The Ti(III) and V(III) complexes are proposed to be a capped octahedron in which a seventh ligand has been added to triangular face. The complexes are non-electrolytes as shown by their molar conductivities (ΛM). The structure of metal complexes is proposed from elemental analysis, FT-IR, UV-vis, magnetic susceptibility measurements, molar conductivity measurements, Mass Spectra and thermal gravimetric analysis. In addition antimicrobial and antioxidant studies, cyclic voltammetry of the complexes, theoretical 1H NMR and HOMO-LUMO energy calculations of the new di-functional ligand were done., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A series of novel 4,5-dihydropyrazole derivatives (4a-4t), containing the dinitrobenzotrifluoride moiety, as DNA gyrase inhibitors were designed and synthesized. Based on the preliminary results, compounds 4d, 4f and 4t with potent inhibitory activity in bacterial growth may be wonderful antibacterial agents; among them, compound 4t displayed the most potent activity with minimum inhibitory concentration (MIC) values of 3.125, 0.39, 0.39 and 0.39 μg mL(-1) against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli respectively, which was comparable with penicillin and kanamycin B with corresponding MIC values of 3.125, 3.125, 0.39, 0.39 μg mL(-1) and 1.562, 1.562, 1.562, 1.562 μg mL(-1), respectively. In particular, compound 4d showed the most potent anti-Gram-positive bacterial activity with a MIC value of 0.39 μg mL(-1) against the tested Gram-positive bacterial strains and exhibited the most potent B. subtilis DNA gyrase and S. aureus DNA gyrase inhibitory activity with an IC50 of 0.125 μg mL(-1). Docking simulation was performed to insert compound 4d into the S. aureus DNA gyrase active site to determine the probable binding conformation.

Phytochemical investigation of the endophytic fungus Coniothyrium sp. resulted in the isolation of a new phenoxyphenyl ether, named coniothyren (1), and two known compounds, coniol (2) and (+)-epoxydon (3). The structure of the new compound was elucidated by detailed spectroscopic analysis, namely, (1)H NMR, (13)C NMR, COSY, HMQC, HMBC, and HR-EI-MS. Preliminary studies demonstrated that (+)-epoxydon (3) displayed good antibacterial and antialgal activities toward Bacillus megaterium and Chlorella fusca, respectively.

In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid.

Four novel inhibitors of the NorA efflux pump of Staphylococcus aureus, discovered through a virtual screening process, are reported. The four compounds belong to different chemical classes and were tested for their in vitro ability to block the efflux of a well-known NorA substrate, as well as for their ability to potentiate the effect of ciprofloxacin (CPX) on several strains of S. aureus, including a NorA overexpressing strain. Additionally, the MIC values of each of the compounds individually are reported. A structure-activity relationship study was also performed on these novel chemotypes, revealing three new compounds that are also potent NorA inhibitors. The virtual screening procedure employed FLAP, a new methodology based on GRID force field descriptors.

Objectives: The National Institute of Allergy and Infectious Disease classifies Francisella tularensis as a Category A priority pathogen. Despite the availability of drugs for treating tularaemia, the mortality in naturally acquired cases can still approach 30%. In addition, the usefulness of existing drugs for treatment in response to exposure or for prophylaxis is limited because of toxicity and delivery concerns. The aim of this study was to assess the efficacy of the lead alkyl-substituted diphenyl ether, SBPT04, in the F. tularensis murine model of infection., Methods: SBPT04 was delivered by intraperitoneal (ip) and oral (po) routes, and mice were monitored for morbidity, mortality and relapse of disease. Pharmacokinetic studies were performed to evaluate bioavailability. Phase I and Phase II metabolism of SBPT04 was assessed in mouse and human microsomes., Results: SBPT04, a potent inhibitor of the enoyl-ACP reductase enzyme ftuFabI, has efficacy against F. tularensis in the murine model of infection when delivered by both ip and po routes. SBPT04 delivered ip cleared infection by day 4 of treatment, and SBPT04 delivered po resulted in delayed dissemination. Importantly, SBPT04 delivered ip or po demonstrated efficacy with no signs of relapse of disease. Pharmacokinetic studies show increased serum concentrations following ip delivery compared with po delivery, which correlates with the observed survival rate of 100%., Conclusions: In addition to being a potent lead, this work substantiates substituted diphenyl ethers as a platform for the development of novel broad-spectrum chemotherapeutics to other bacterial agents in addition to F. tularensis.

A series of dicationic diaryl ethers have been synthesized and evaluated for in vitro antibacterial activities, including drug resistant bacterial strains. Most of these compounds have shown potent antibacterial activities. Several compounds, such as piperidinyl and thiomorpholinyl compounds 9e and 9l, improved the antimicrobial selectivity and kept potent anti-MRSA and anti-VRE activity. The most potent bis-indole diphenyl ether 19 exhibited anti-MRSA MIC value of 0.06 microg/mL and enhanced antimicrobial selectivity.

Francisella tularensis is a highly virulent and contagious Gram-negative intracellular bacterium that causes the disease tularemia in mammals. The high infectivity and the ability of the bacterium to survive for weeks in a cool, moist environment have raised the possibility that this organism could be exploited deliberately as a potential biological weapon. Fatty acid biosynthesis (FAS-II) is essential for bacterial viability and has been validated as a target for the discovery of novel antibacterials. The FAS-II enoyl reductase ftuFabI has been cloned and expressed, and a series of diphenyl ethers have been identified that are subnanomolar inhibitors of the enzyme with MIC90 values as low as 0.00018 microg mL(-1). The existence of a linear correlation between the Ki and MIC values strongly suggests that the antibacterial activity of the diphenyl ethers results from direct inhibition of ftuFabI within the cell. The compounds are slow-onset inhibitors of ftuFabI, and the residence time of the inhibitors on the enzyme correlates with their in vivo activity in a mouse model of tularemia infection. Significantly, the rate of breakdown of the enzyme-inhibitor complex is a better predictor of in vivo activity than the overall thermodynamic stability of the complex, a concept that has important implications for the discovery of novel chemotherapeutics that normally rely on equilibrium measurements of potency.

Previous structure-based design studies resulted in the discovery of alkyl substituted diphenyl ether inhibitors of InhA, the enoyl reductase from Mycobacterium tuberculosis. Compounds such as 5-hexyl-2-phenoxyphenol 19 are nM inhibitors of InhA and inhibit the growth of both sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis with MIC(90) values of 1-2 microg/mL. However, despite their promising in vitro activity, these compounds have ClogP values of over 5. In efforts to reduce the lipophilicity of the compounds, and potentially enhance compound bioavailability, a series of B ring analogues of 19 were synthesized that contained either heterocylic nitrogen rings or phenyl rings having amino, nitro, amide, or piperazine functionalities. Compounds 3c, 3e, and 14a show comparable MIC(90) values to that of 19, but have improved ClogP values.

Two novel diphenyl ether glycosides and a new diphenyl ether, cordyol A-C (1-3), were isolated from the insect pathogenic fungus Cordyceps sp. BCC 1861. Structures of these compounds were elucidated by NMR and MS spectral analyses. Cordyol C (3) exhibited significant anti-HSV-1 activity with an IC50 value of 1.3 microg/ml, and cytotoxic activity against BC and NCI-H187 cancer cell lines with IC50 values of 8.65 and 3.72 microg/ml, respectively. Cordyol A (1) displayed weak antimycobacterial activity with a MIC value of 100 microg/ml.

In a screening of basidiomycete cultures from Chile for the production of antibiotics we identified a Serpula himantoides strain as a producer of metabolites inhibiting the growth of bacteria and fungi. Bioactivity guided purification resulted in the isolation of four new antibiotics. Their structures were elucidated by spectroscopic methods. All four compounds are succinimide and maleimide derivatives, of which two are N-hydroxylated.

ZM240304 is an example of a new class of antibacterial agents that is active against experimental infections in animals. The compound was demonstrated to be a membrane-active compound that disrupted the outer membrane of Gram-negative organisms and allowed the leakage of periplasmic enzymes. Respiration was inhibited and cellular ATP levels were reduced, leading to cell death. The ability of the bacteria to take up small molecules such as amino acids and sugars was inhibited, probably by interference with inner membrane function.