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25 pages, 987 KB

Open AccessReview

Broad-Spectrum Anti-Infective Activity of Natural Compounds Pyrrolomycins, Marinopyrroles, and Their Analogs

by Brianna N. Davis, Clare F. Euteneuer, Kayleen J. Mijangos, Angelique Vargas, Kailey M. Bruha and Paul H. Davis

Pathogens 2026, 15(2), 203; https://doi.org/10.3390/pathogens15020203 - 11 Feb 2026

Viewed by 733

Abstract

Pyrrolomycins and marinopyrroles are natural products originally derived from Streptomyces spp. that possess potent anti-infective activity against a variety of organisms, including drug-resistant bacteria and eukaryotic pathogens, especially pertinent amid the search for additional antimicrobial agents. These highly halogenated compounds have been proposed [...] Read more.

Pyrrolomycins and marinopyrroles are natural products originally derived from Streptomyces spp. that possess potent anti-infective activity against a variety of organisms, including drug-resistant bacteria and eukaryotic pathogens, especially pertinent amid the search for additional antimicrobial agents. These highly halogenated compounds have been proposed to act as protonophores, an uncommon mechanism of action that likely contributes to their broad-spectrum antibacterial activity. To improve efficacy and overcome limitations to clinical transition, promising derivatives of these natural compounds have been synthesized, introducing structural refinements that enhance pharmacological properties while preserving potent anti-infective activity. Recent discoveries demonstrate the potential of pyrrolomycins and marinopyrroles derivatives to serve as broad-spectrum anti-infective agents with efficacy against drug-resistant bacteria, bacterial biofilms, parasitic infections, and some viruses. Full article

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34 pages, 4384 KB

Open AccessReview

Cancer Cell Cytotoxicity of Marinopyrroles, Pyrrolomycins, and Their Derivatives

by Jeffrey M. Zimmerly, Nicholas A. Armstrong, Clare F. Euteneuer, Brianna N. Davis, M. Beth Griffis-Anchala, Angelique Vargas and Paul H. Davis

Mar. Drugs 2025, 23(10), 403; https://doi.org/10.3390/md23100403 - 16 Oct 2025

Cited by 1 | Viewed by 1715

Abstract

Marine-derived secondary metabolites have emerged as a rich potential source of anticancer agents, with marinopyrroles and pyrrolomycins representing structurally distinct halogenated pyrroles of interest. Initially characterized for their potent antibacterial properties, these compounds were later shown to exert cytotoxic activity across diverse hematologic [...] Read more.

Marine-derived secondary metabolites have emerged as a rich potential source of anticancer agents, with marinopyrroles and pyrrolomycins representing structurally distinct halogenated pyrroles of interest. Initially characterized for their potent antibacterial properties, these compounds were later shown to exert cytotoxic activity across diverse hematologic and solid malignancies, frequently correlating with Mcl-1 dependence. Marinopyrrole A, a marine-derived natural product, exemplified this potential by inducing proteasomal degradation of Mcl-1, thereby sensitizing resistant cancer cells to Bcl-2 inhibitors and TRAIL-based therapies. In parallel, pyrrolomycins, particularly pyrrolomycin C and members of the F-series, demonstrated potent activity with submicromolar IC₅₀ concentrations across multiple cancer cell lines, and also perturbed cytoskeletal and membrane integrity. Together, these halogenated pyrroles illustrate multifaceted cancer cell cytotoxicity profiles but face translational barriers, including mechanistic ambiguity, poor solubility, and off-target toxicities. To address these limitations, extensive medicinal chemistry efforts have yielded synthetic derivatives with improved potency, selectivity, and drug-like properties, with notable examples such as MP1 and KS18 showing enhanced efficacy in MYC-driven neuroblastoma, medulloblastoma, and drug-resistant multiple myeloma. Full article

(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents, 5th Edition)

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15 pages, 1111 KB

Open AccessArticle

Expanded Gram-Negative Activity of Marinopyrrole A

by Clare F. Euteneuer, Brianna N. Davis, LeeAnna M. Lui, Andrew J. Neville and Paul H. Davis

Pathogens 2025, 14(3), 290; https://doi.org/10.3390/pathogens14030290 - 16 Mar 2025

Cited by 2 | Viewed by 1888

Abstract

The rise of bacterial infections is a global health issue that calls for the development and availability of additional antimicrobial agents. Known for its in vitro effects on Gram-positive organisms, the drug-like small molecule marinopyrrole A was re-examined for the potential of broader [...] Read more.

The rise of bacterial infections is a global health issue that calls for the development and availability of additional antimicrobial agents. Known for its in vitro effects on Gram-positive organisms, the drug-like small molecule marinopyrrole A was re-examined for the potential of broader efficacy against a wider array of microbes. We uncovered selective efficacy against an important subset of Gram-negative bacteria from three genera: Neisseria, Moraxella, and Campylobacter. This susceptibility is correlated with the absence of canonical LPS in these specific Gram-negative species, a phenomenon observed with other hydrophobic anti-microbial compounds. Further, when exposed to molecules which inhibit the LpxC enzyme of the LPS synthesis pathway, previously resistant LPS-producing Gram-negative bacteria showed increased susceptibility to marinopyrrole A. These results demonstrate marinopyrrole A’s efficacy against a broader range of Gram-negative bacteria than previously known, including N. gonorrhea, a species identified as a priority pathogen by the WHO. Full article

(This article belongs to the Section Bacterial Pathogens)

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40 pages, 8195 KB

Open AccessReview

Unlocking the Potential of Pyrrole: Recent Advances in New Pyrrole-Containing Compounds with Antibacterial Potential

by Aura Rusu, Octavia-Laura Oancea, Corneliu Tanase and Livia Uncu

Int. J. Mol. Sci. 2024, 25(23), 12873; https://doi.org/10.3390/ijms252312873 - 29 Nov 2024

Cited by 21 | Viewed by 23166

Abstract

Nitrogen heterocycles are valuable structural elements in the molecules of antibacterial drugs approved and used to treat bacterial infections. Pyrrole is a five-atom heterocycle found in many natural compounds with biological activity, including antibacterial activity. Numerous compounds are being develop based on the [...] Read more.

Nitrogen heterocycles are valuable structural elements in the molecules of antibacterial drugs approved and used to treat bacterial infections. Pyrrole is a five-atom heterocycle found in many natural compounds with biological activity, including antibacterial activity. Numerous compounds are being develop based on the pyrrole heterocycle as new potential antibacterial drugs. Due to the phenomenon of antibacterial resistance, there is a continuous need to create new effective antibacterials. In the scientific literature, we have identified the most relevant studies that aim to develop new compounds, such as pyrrole derivatives, that are proven to have antibacterial activity. Nature is an endless reservoir of inspiration for designing new compounds based on the structure of pyrrole heterocycles such as calcimycin, lynamycins, marinopyrroles, nargenicines, phallusialides, and others. However, many other synthetic compounds based on the pyrrole heterocycle have been developed and can be optimized in the future. The identified compounds were classified according to the type of chemical structure. The chemical structure–activity relationships, mechanisms of action, and antibacterial effectiveness of the most valuable compounds were highlighted. This review highlights scientific progress in designing new pyrrole-containing compounds and provides examples of lead compounds that can be successfully optimized further. Full article

(This article belongs to the Topic Designing New Antimicrobials Based on Known Valuable Heterocycles as Building Blocks)

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19 pages, 1910 KB

Open AccessArticle

Assessment of Tissue Distribution and Metabolism of MP1, a Novel Pyrrolomycin, in Mice Using a Validated LC-MS/MS Method

by Wafaa N. Aldhafiri, Yashpal S. Chhonker, Yuning Zhang, Don W. Coulter, Timothy R. McGuire, Rongshi Li and Daryl J. Murry

Molecules 2020, 25(24), 5898; https://doi.org/10.3390/molecules25245898 - 13 Dec 2020

Cited by 11 | Viewed by 3561

Abstract

MP1 is a novel marinopyrrole analogue with activity in MYCN amplified neuroblastoma cell lines. A rapid, selective, and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantitation of MP1 in mouse plasma. Analyte separation was achieved [...] Read more.

MP1 is a novel marinopyrrole analogue with activity in MYCN amplified neuroblastoma cell lines. A rapid, selective, and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantitation of MP1 in mouse plasma. Analyte separation was achieved using a Waters Acquity UPLC^®BEH C18 column (1.7 µm, 100 × 2.1 mm). Mobile phase consisted of 0.1% acetic acid in water (10%) and methanol (90%) at a total flow rate of 0.25 mL/min. The mass spectrometer was operated at unit resolution in the multiple reaction monitoring (MRM) mode, using precursor ion > product ion transitions of 324.10 > 168.30 m/z for MP1 and 411.95 > 224.15 m/z for PL-3. The MS/MS response was linear over the concentration range from 0.2–500 ng/mL for MP1, correlation coefficient (r²) of 0.988. Precision (% RSD) and accuracy (% bias) were within the acceptable limits as per FDA guidelines. MP1 was stable under storage and laboratory handling conditions. The validated method was successfully applied to assess the solubility, in-vitro metabolism, plasma protein binding, and bio-distribution studies of MP1. Full article

(This article belongs to the Section Analytical Chemistry)

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15 pages, 1006 KB

Open AccessArticle

Marinopyrrole Derivatives with Sulfide Spacers as Selective Disruptors of Mcl-1 Binding to Pro-Apoptotic Protein Bim

by Chunwei Cheng, Yan Liu, Maria E. Balasis, Thomas P. Garner, Jerry Li, Nicholas L. Simmons, Norbert Berndt, Hao Song, Lili Pan, Yong Qin, K. C. Nicolaou, Evripidis Gavathiotis, Said M. Sebti and Rongshi Li

Mar. Drugs 2014, 12(8), 4311-4325; https://doi.org/10.3390/md12084311 - 29 Jul 2014

Cited by 14 | Viewed by 9463

Abstract

A series of novel marinopyrroles with sulfide and sulphone spacers were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-xL, was evaluated using ELISA assays. Fluorescence-quenching (FQ) assays confirmed the direct [...] Read more.

A series of novel marinopyrroles with sulfide and sulphone spacers were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-xL, was evaluated using ELISA assays. Fluorescence-quenching (FQ) assays confirmed the direct binding of marinopyrroles to Mcl-1. Benzyl- and benzyl methoxy-containing sulfide derivatives 4 and 5 were highly potent dual Mcl-1/Bim and Bcl-xL/Bim disruptors (IC₅₀ values of 600 and 700 nM), whereas carboxylate-containing sulfide derivative 9 exhibited 16.4-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding. In addition, a nonsymmetrical marinopyrrole 12 is as equally potent as the parent marinopyrrole A (1) for disrupting both Mcl-1/Bim and Bcl-xL/Bim binding. Some of the derivatives were also active in intact human breast cancer cells where they reduced the levels of Mcl-1, induced programd cell death (apoptosis) and inhibited cell proliferation. Full article

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13 pages, 848 KB

Open AccessArticle

Marinopyrrole Derivatives as Potential Antibiotic Agents against Methicillin-Resistant Staphylococcus aureus (III)

by Yan Liu, Nina M. Haste, Wdee Thienphrapa, Jerry Li, Victor Nizet, Mary Hensler and Rongshi Li

Mar. Drugs 2014, 12(5), 2458-2470; https://doi.org/10.3390/md12052458 - 30 Apr 2014

Cited by 18 | Viewed by 6524

Abstract

The marine natural product, marinopyrrole A (1), was previously shown to have significant antibiotic activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Although compound (1) exhibits a significant reduction in MRSA activity in the presence of human serum, [...] Read more.

The marine natural product, marinopyrrole A (1), was previously shown to have significant antibiotic activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Although compound (1) exhibits a significant reduction in MRSA activity in the presence of human serum, we have identified key modifications that partially restore activity. We previously reported our discovery of a chloro-derivative of marinopyrrole A (1a) featuring a 2–4 fold improved minimum inhibitory concentration (MIC) against MRSA, significantly less susceptibility to serum inhibition and rapid and concentration-dependent killing of MRSA. Here, we report a novel fluoro-derivative of marinopyrrole A (1e) showing an improved profile of potency, less susceptibility to serum inhibition, as well as rapid and concentration-dependent killing of MRSA. Full article

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14 pages, 904 KB

Open AccessArticle

Cyclic Marinopyrrole Derivatives as Disruptors of Mcl-1 and Bcl-x_L Binding to Bim

by Chunwei Cheng, Yan Liu, Maria E. Balasis, Nicholas L. Simmons, Jerry Li, Hao Song, Lili Pan, Yong Qin, K. C. Nicolaou, Said M. Sebti and Rongshi Li

Mar. Drugs 2014, 12(3), 1335-1348; https://doi.org/10.3390/md12031335 - 7 Mar 2014

Cited by 19 | Viewed by 8458

Abstract

A series of novel cyclic marinopyrroles were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-x_L, was evaluated using ELISA assays. Both atropisomers of marinopyrrole A (1) [...] Read more.

A series of novel cyclic marinopyrroles were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-x_L, was evaluated using ELISA assays. Both atropisomers of marinopyrrole A (1) show similar potency. A tetrabromo congener 9 is two-fold more potent than 1. Two novel cyclic marinopyrroles (3 and 4) are two- to seven-fold more potent than 1. Full article

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22 pages, 911 KB

Open AccessArticle

Marinopyrrole Derivatives as Potential Antibiotic Agents against Methicillin-Resistant Staphylococcus aureus (II)

by Chunwei Cheng, Yan Liu, Hao Song, Lili Pan, Jerry Li, Yong Qin and Rongshi Li

Mar. Drugs 2013, 11(8), 2927-2948; https://doi.org/10.3390/md11082927 - 15 Aug 2013

Cited by 29 | Viewed by 9904

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major problem, causing severe and intractable infections worldwide. MRSA is resistant to all beta-lactam antibiotics, and alternative treatments are limited. A very limited number of new antibiotics have been discovered over the last half-century, novel [...] Read more.

Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major problem, causing severe and intractable infections worldwide. MRSA is resistant to all beta-lactam antibiotics, and alternative treatments are limited. A very limited number of new antibiotics have been discovered over the last half-century, novel agents for the treatment of MRSA infections are urgently needed. Marinopyrrole A was reported to show antibiotic activity against MRSA in 2008. After we reported the first total synthesis of (±)-marinopyrrole A, we designed and synthesized a series of marinopyrrole derivatives. Our structure activity relationship (SAR) studies of these novel derivatives against a panel of Gram-positive pathogens in antibacterial assays have revealed that a para-trifluoromethyl analog (33) of marinopyrrole A is ≥63-, 8-, and 4-fold more potent than vancomycin against methicillin-resistant Staphylococcus epidermidis (MRSE), methicillin-susceptible Staphylococcus aureus (MSSA) and MRSA, respectively. The results provide valuable information in the search for new-generation antibiotics. Full article

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10 pages, 311 KB

Open AccessArticle

Marinopyrrole Derivatives as Potential Antibiotic Agents against Methicillin-Resistant Staphylococcus aureus (I)

by Yan Liu, Nina M. Haste, Wdee Thienphrapa, Victor Nizet, Mary Hensler and Rongshi Li

Mar. Drugs 2012, 10(4), 953-962; https://doi.org/10.3390/md10040953 - 24 Apr 2012

Cited by 22 | Viewed by 8264

Abstract

Infections caused by drug-resistant pathogens are on the rise. The ongoing spread of methicillin-resistant Staphylococcus aureus (MRSA) strains exemplifies the urgent need for new antibiotics. The marine natural product, marinopyrrole A, was previously shown to have potent antibiotic activity against Gram-positive pathogens, including [...] Read more.

Infections caused by drug-resistant pathogens are on the rise. The ongoing spread of methicillin-resistant Staphylococcus aureus (MRSA) strains exemplifies the urgent need for new antibiotics. The marine natural product, marinopyrrole A, was previously shown to have potent antibiotic activity against Gram-positive pathogens, including MRSA. However, its minimum inhibitory concentration (MIC) against MRSA was increased by >500 fold in the presence of 20% human serum, thus greatly limiting therapeutic potential. Here we report our discovery of a novel derivative of marinopyrrole A, designated 1a, featuring a 2–4 fold improved MIC against MRSA and significantly less susceptibility to serum inhibition. Importantly, compound 1a displayed rapid and concentration-dependent killing of MRSA. Compared to the natural product counterpart, compound 1a provides an important natural product based scaffold for further Structure Activity Relationship (SAR) and optimization. Full article

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