Discovery of Biofilm-Inhibiting Compounds to Enhance Antibiotic Effectiveness Against <i>M. abscessus</i> Infections
<b>Background/Objectives</b>: <i>Mycobacterium abscessus</i> (MAB) is a highly resilient pathogen that causes difficult-to-treat pulmonary infections, particularly in individuals with cystic fibrosis (CF) and other underlying conditions. Its ability to form robust biofilms wi...
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MDPI AG
2025-02-01
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| author | Elizaveta Dzalamidze Mylene Gorzynski Rebecca Vande Voorde Dylan Nelson Lia Danelishvili |
| author_facet | Elizaveta Dzalamidze Mylene Gorzynski Rebecca Vande Voorde Dylan Nelson Lia Danelishvili |
| author_sort | Elizaveta Dzalamidze |
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| description | <b>Background/Objectives</b>: <i>Mycobacterium abscessus</i> (MAB) is a highly resilient pathogen that causes difficult-to-treat pulmonary infections, particularly in individuals with cystic fibrosis (CF) and other underlying conditions. Its ability to form robust biofilms within the CF lung environment is a major factor contributing to its resistance to antibiotics and evasion of the host immune response, making conventional treatments largely ineffective. These biofilms, encased in an extracellular matrix, enhance drug tolerance and facilitate metabolic adaptations in hypoxic conditions, driving the bacteria into a persistent, non-replicative state that further exacerbates antimicrobial resistance. Treatment options remain limited, with multidrug regimens showing low success rates, highlighting the urgent need for more effective therapeutic strategies. <b>Methods</b>: In this study, we employed artificial sputum media to simulate the CF lung environment and conducted high-throughput screening of 24,000 compounds from diverse chemical libraries to identify inhibitors of MAB biofilm formation, using the Crystal Violet (CV) assay. <b>Results</b>: The screen established 17 hits with ≥30% biofilm inhibitory activity in mycobacteria. Six of these compounds inhibited MAB biofilm formation by over 60%, disrupted established biofilms by ≥40%, and significantly impaired bacterial viability within the biofilms, as confirmed by reduced CFU counts. In conformational assays, select compounds showed potent inhibitory activity in biofilms formed by clinical isolates of both MAB and <i>Mycobacterium avium</i> subsp. <i>hominissuis</i> (MAH). Key compounds, including ethacridine, phenothiazine, and fluorene derivatives, demonstrated potent activity against pre- and post-biofilm conditions, enhanced antibiotic efficacy, and reduced intracellular bacterial loads in macrophages. <b>Conclusions</b>: This study results underscore the potential of these compounds to target biofilm-associated resistance mechanisms, making them valuable candidates for use as adjuncts to existing therapies. These findings also emphasize the need for further investigations, including the initiation of a medicinal chemistry campaign to leverage structure–activity relationship studies and optimize the biological activity of these underexplored class of compounds against nontuberculous mycobacterial (NTM) strains. |
| format | Article |
| id | doaj-art-8fb7b52f822c4a33a994087a2aca475f |
| institution | DOAJ |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | MDPI AG |
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| spelling | doaj-art-8fb7b52f822c4a33a994087a2aca475f2025-08-20T02:45:01ZengMDPI AGPharmaceuticals1424-82472025-02-0118222510.3390/ph18020225Discovery of Biofilm-Inhibiting Compounds to Enhance Antibiotic Effectiveness Against <i>M. abscessus</i> InfectionsElizaveta Dzalamidze0Mylene Gorzynski1Rebecca Vande Voorde2Dylan Nelson3Lia Danelishvili4Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USADepartment of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USADepartment of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USADepartment of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USADepartment of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA<b>Background/Objectives</b>: <i>Mycobacterium abscessus</i> (MAB) is a highly resilient pathogen that causes difficult-to-treat pulmonary infections, particularly in individuals with cystic fibrosis (CF) and other underlying conditions. Its ability to form robust biofilms within the CF lung environment is a major factor contributing to its resistance to antibiotics and evasion of the host immune response, making conventional treatments largely ineffective. These biofilms, encased in an extracellular matrix, enhance drug tolerance and facilitate metabolic adaptations in hypoxic conditions, driving the bacteria into a persistent, non-replicative state that further exacerbates antimicrobial resistance. Treatment options remain limited, with multidrug regimens showing low success rates, highlighting the urgent need for more effective therapeutic strategies. <b>Methods</b>: In this study, we employed artificial sputum media to simulate the CF lung environment and conducted high-throughput screening of 24,000 compounds from diverse chemical libraries to identify inhibitors of MAB biofilm formation, using the Crystal Violet (CV) assay. <b>Results</b>: The screen established 17 hits with ≥30% biofilm inhibitory activity in mycobacteria. Six of these compounds inhibited MAB biofilm formation by over 60%, disrupted established biofilms by ≥40%, and significantly impaired bacterial viability within the biofilms, as confirmed by reduced CFU counts. In conformational assays, select compounds showed potent inhibitory activity in biofilms formed by clinical isolates of both MAB and <i>Mycobacterium avium</i> subsp. <i>hominissuis</i> (MAH). Key compounds, including ethacridine, phenothiazine, and fluorene derivatives, demonstrated potent activity against pre- and post-biofilm conditions, enhanced antibiotic efficacy, and reduced intracellular bacterial loads in macrophages. <b>Conclusions</b>: This study results underscore the potential of these compounds to target biofilm-associated resistance mechanisms, making them valuable candidates for use as adjuncts to existing therapies. These findings also emphasize the need for further investigations, including the initiation of a medicinal chemistry campaign to leverage structure–activity relationship studies and optimize the biological activity of these underexplored class of compounds against nontuberculous mycobacterial (NTM) strains.https://www.mdpi.com/1424-8247/18/2/225<i>Mycobacterium abscessus</i>nontuberculous mycobacteriaNTMhigh-throughput screeningsmall moleculesbiofilm |
| spellingShingle | Elizaveta Dzalamidze Mylene Gorzynski Rebecca Vande Voorde Dylan Nelson Lia Danelishvili Discovery of Biofilm-Inhibiting Compounds to Enhance Antibiotic Effectiveness Against <i>M. abscessus</i> Infections Pharmaceuticals <i>Mycobacterium abscessus</i> nontuberculous mycobacteria NTM high-throughput screening small molecules biofilm |
| title | Discovery of Biofilm-Inhibiting Compounds to Enhance Antibiotic Effectiveness Against <i>M. abscessus</i> Infections |
| title_full | Discovery of Biofilm-Inhibiting Compounds to Enhance Antibiotic Effectiveness Against <i>M. abscessus</i> Infections |
| title_fullStr | Discovery of Biofilm-Inhibiting Compounds to Enhance Antibiotic Effectiveness Against <i>M. abscessus</i> Infections |
| title_full_unstemmed | Discovery of Biofilm-Inhibiting Compounds to Enhance Antibiotic Effectiveness Against <i>M. abscessus</i> Infections |
| title_short | Discovery of Biofilm-Inhibiting Compounds to Enhance Antibiotic Effectiveness Against <i>M. abscessus</i> Infections |
| title_sort | discovery of biofilm inhibiting compounds to enhance antibiotic effectiveness against i m abscessus i infections |
| topic | <i>Mycobacterium abscessus</i> nontuberculous mycobacteria NTM high-throughput screening small molecules biofilm |
| url | https://www.mdpi.com/1424-8247/18/2/225 |
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