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1. Highlighting the Biotechnological Potential of Deep Oceanic Crust Fungi through the Prism of Their Antimicrobial Activity

   https://doi.org/10.3390/md19080411  

   Quemener, Maxence; Dayras, Marie; Frotté, Nicolas; Debaets, Stella; Le Meur, Christophe; Barbier, Georges; Edgcomb, Virginia; Mehiri, Mohamed; Burgaud, Gaëtan (August 2021, Marine Drugs)

   null (Ed.)

   Among the different tools to address the antibiotic resistance crisis, bioprospecting in complex uncharted habitats to detect novel microorganisms putatively producing original antimicrobial compounds can definitely increase the current therapeutic arsenal of antibiotics. Fungi from numerous habitats have been widely screened for their ability to express specific biosynthetic gene clusters (BGCs) involved in the synthesis of antimicrobial compounds. Here, a collection of unique 75 deep oceanic crust fungi was screened to evaluate their biotechnological potential through the prism of their antimicrobial activity using a polyphasic approach. After a first genetic screening to detect specific BGCs, a second step consisted of an antimicrobial screening that tested the most promising isolates against 11 microbial targets. Here, 12 fungal isolates showed at least one antibacterial and/or antifungal activity (static or lytic) against human pathogens. This analysis also revealed that Staphylococcus aureus ATCC 25923 and Enterococcus faecalis CIP A 186 were the most impacted, followed by Pseudomonas aeruginosa ATCC 27853. A specific focus on three fungal isolates allowed us to detect interesting activity of crude extracts against multidrug-resistant Staphylococcus aureus. Finally, complementary mass spectrometry (MS)-based molecular networking analyses were performed to putatively assign the fungal metabolites and raise hypotheses to link them to the observed antimicrobial activities. 

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2. High-Throughput Screen for Inhibitors of the Type IV Pilus Assembly ATPase PilB

   https://doi.org/10.1128/mSphere.00129-21  

   Dye, Keane J.; Vogelaar, Nancy J.; Sobrado, Pablo; Yang, Zhaomin (April 2021, mSphere)

   Dunman, Paul (Ed.)

   ABSTRACT The bacterial type IV pilus (T4P) is a prominent virulence factor in many significant human pathogens, some of which have become increasingly antibiotic resistant. Antivirulence chemotherapeutics are considered a promising alternative to antibiotics because they target the disease process instead of bacterial viability. However, a roadblock to the discovery of anti-T4P compounds is the lack of a high-throughput screen (HTS) that can be implemented relatively easily and economically. Here, we describe the first HTS for the identification of inhibitors specifically against the T4P assembly ATPase PilB in vitro . Chloracidobacterium thermophilum PilB ( Ct PilB) had been demonstrated to have robust ATPase activity and the ability to bind its expected ligands in vitro. We utilized Ct PilB and MANT-ATP, a fluorescent ATP analog, to develop a binding assay and adapted it for an HTS. As a proof of principle, we performed a pilot screen with a small compound library of kinase inhibitors and identified quercetin as a PilB inhibitor in vitro . Using Myxococcus xanthus as a model bacterium, we found quercetin to reduce its T4P-dependent motility and T4P assembly in vivo. These results validated our HTS as effective in identifying PilB inhibitors. This assay may prove valuable in seeking leads for the development of antivirulence chemotherapeutics against PilB, an essential and universal component of all bacterial T4P systems. IMPORTANCE Many bacterial pathogens use their type IV pili (T4P) to facilitate and maintain infection of a human host. Small chemical compounds that inhibit the production or assembly of T4P hold promise in the treatment and prevention of infections, especially in the era of increasing threats from antibiotic-resistant bacteria. However, few chemicals are known to have inhibitory or anti-T4P activity. Their identification has not been easy due to the lack of a method for the screening of compound collections or libraries on a large scale. Here, we report the development of an assay that can be scaled up to screen compound libraries for inhibitors of a critical T4P assembly protein. We further demonstrate that it is feasible to use whole cells to examine potential inhibitors for their activity against T4P assembly in a bacterium. 

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3. Investigating Soil Microbiota for Antimicrobial Activity Against Safe Relatives of ESKAPE Pathogens

   Kim, E; O'besso, A; Graham, D; Graham, J (July 2025, Atlas journal of biology)

   According to the CDC, there are more than 2.8 million antibiotic resistant infections occurring in the United States each year, and more than 35,000 people die as a result (CDC 2019). Furthermore, the CDC classifies a group of bacteria known as ESKAPE pathogens as six emerging antibiotic-resistant pathogens that are difficult to eradicate with current antibiotics. Our study aims to identify and characterize soil-derived microorganisms with the potential to produce antimicrobial compounds effective against safe relatives of ESKAPE pathogens, with the goal of translating these findings to combat their pathogenic counterparts. We hypothesize that bacteria identified from the soil will inhibit the growth of the following nosocomial associated safe relatives Bacillus subtilis for E. faecium, Staphylococcus epidermidis for S. aureus, Escherichia coli for Klebsiella pneumoniae, Acinetobacter baylyi for A. baumannii, Pseudomonas putida for P. aeruginosa, and Enterobacter aerogenes for Enterobacter species. To test our hypothesis, soil samples were collected from Fayetteville State University (FSU) campus and serially diluted onto LB agar plates. Sixty-three distinct colonies were isolated and screened against non-pathogenic ESKAPE safe relatives. Of the 63 Fayetteville State University soil isolates (FSIs) screened, 12 (19%) exhibited antimicrobial activity against at least one of the six ESKAPE safe relatives, with all 12 inhibiting Acinetobacter baylyi and only FSI 15 demonstrating broad-spectrum inhibition. Characterization assays revealed that 11 of the 12 isolates were Gram-negative, catalase-positive, and motile; the single Gram-positive isolate (FSI 4) was catalase-negative and non-motile. All isolates displayed resistance to penicillin, while most remained susceptible to tetracycline and ciprofloxacin. These findings support our hypothesis that soil-derived bacteria can produce putative antimicrobial compounds effective against non-pathogenic ESKAPE safe relatives. This study underscores the potential of soil microbiota on the campus of Fayetteville State University as a source of novel antimicrobial agents capable of inhibiting antibiotic resistant ESKAPE pathogens and warrant further investigation into their therapeutic potential 

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4. Synthesis of Thiazole‐Fused Diosgenin Derivatives as Potential Therapeutic Agents

   https://doi.org/10.1002/slct.202402485  

   Roy, Subrata; Budhathoki, Shailesh; Alam, Mohammad Abrar (October 2024, ChemistrySelect)

   Abstract Diosgenin, a hydrolyzed product of phytosteroid saponin, has widely been studied for its medicinal properties. In an effort to find bioactive molecules, 25 novel thiazole‐fused diosgenin molecules have been synthesized by an efficient reaction protocol. The chemistry involves the Oppenauer oxidation followed by double bond isomerization in a one‐pot reaction, epoxidation, and the reaction of urea derivatives with the epoxyketone to synthesize the target compounds. These novel chimeric compounds were tested for their potential antimicrobial and cytotoxic properties. Antimicrobial studies against a panel of Gram‐positive and Gram‐negative led to the discovery of some of these molecules as narrow‐spectrum antimicrobial agents againstBacillus subtilisbacteria. In preliminary cytotoxicity studies, 2‐fluorophenyl derivative (10) inhibited the growth of several cell lines of the NCI‐60 cell line panels including >93 % inhibition of UO‐31 cell line. Furthermore, the hit antibacterial compounds are non‐toxic to human cancer cell lines, and the cytotoxic compound is not active against the bacterial strains, showing the selective therapeutic potential of the chimeric compounds. 

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5. Biomimetic antimicrobial polymers—Design, characterization, antimicrobial, and novel applications

   https://doi.org/10.1002/wnan.1866  

   Takahashi, Haruko; Sovadinova, Iva; Yasuhara, Kazuma; Vemparala, Satyavani; Caputo, Gregory A.; Kuroda, Kenichi (October 2022, WIREs Nanomedicine and Nanobiotechnology)

   Abstract Biomimetic antimicrobial polymers have been an area of great interest as the need for novel antimicrobial compounds grows due to the development of resistance. These polymers were designed and developed to mimic naturally occurring antimicrobial peptides in both physicochemical composition and mechanism of action. These antimicrobial peptide mimetic polymers have been extensively investigated using chemical, biophysical, microbiological, and computational approaches to gain a deeper understanding of the molecular interactions that drive function. These studies have helped inform SARs, mechanism of action, and general physicochemical factors that influence the activity and properties of antimicrobial polymers. However, there are still lingering questions in this field regarding 3D structural patterning, bioavailability, and applicability to alternative targets. In this review, we present a perspective on the development and characterization of several antimicrobial polymers and discuss novel applications of these molecules emerging in the field. This article is categorized under:Therapeutic Approaches and Drug Discovery > Emerging TechnologiesTherapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease 

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