{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T04:11:40Z","timestamp":1784952700278,"version":"3.55.0"},"reference-count":104,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Chronic bacterial infections are responsible for significant morbidity and mortality in cystic fibrosis (CF) patients. <jats:italic>Pseudomonas aeruginosa<\/jats:italic> (<jats:italic>Pa<\/jats:italic>), the dominant CF pathogen, and <jats:italic>Mycobacterium abscessus<\/jats:italic> (<jats:italic>Mab<\/jats:italic>) can individually cause persistent, difficult to treat pulmonary infections. Co-infection by both pathogens leads to severe disease and poor clinical outcomes. Although interactions between <jats:italic>Pa<\/jats:italic> and other co-infecting pathogens in CF patients have been the focus of numerous studies, the dynamics of <jats:italic>Pa-Mab<\/jats:italic> interactions remain poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To address this knowledge gap, the study examined how <jats:italic>Mab<\/jats:italic> and <jats:italic>Pa<\/jats:italic> influenced each other through culture-based growth assays and molecular-based dual RNAseq analysis. Growth was measured by CFU determination and luminescence reporter -based readouts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In initial studies, we noted that the growth of <jats:italic>Pa<\/jats:italic> continued unimpeded in a planktonic co-culture model, whereas <jats:italic>Pa<\/jats:italic> appeared to exert a bacteriostatic effect on <jats:italic>Mab<\/jats:italic>. Strikingly, exposure of <jats:italic>Mab<\/jats:italic> to cell-free spent supernatant of <jats:italic>Pa<\/jats:italic> resulted in a dramatic, dose-dependent bactericidal effect. Initial characterization indicated that this potent <jats:italic>Pa<\/jats:italic>-derived anti-<jats:italic>Mab<\/jats:italic> cidal activity was mediated by a heat-sensitive, protease-insensitive soluble factor of &amp;gt;3kDa size. Further analysis demonstrated that expression of this mycobactericidal factor requires LasR, a central regulator of <jats:italic>Pa<\/jats:italic> quorum sensing (QS). In contrast, \u0394LasR <jats:italic>Pa<\/jats:italic> was still able to exert a bacteriostatic effect on Mab during co-culture, pointing to additional LasR-independent factors able to antagonize <jats:italic>Mab<\/jats:italic> growth. However, the ability of <jats:italic>Mab<\/jats:italic> to adapt during co-culture to counter the cidal effects of a LasR regulated factor suggested complex interspecies dynamics. Dual RNAseq analysis of <jats:italic>Mab<\/jats:italic>-<jats:italic>Pa<\/jats:italic> co-cultures revealed significant transcriptional remodeling of <jats:italic>Mab<\/jats:italic>, with differential expression of 68% of <jats:italic>Mab<\/jats:italic> genes compared to minimal transcriptional changes in <jats:italic>Pa<\/jats:italic>. Transcriptome analysis reflected slowed <jats:italic>Mab<\/jats:italic> growth and metabolic changes akin to a non-replicating persister phase. A tailored <jats:italic>Mab<\/jats:italic> response to <jats:italic>Pa<\/jats:italic> was evident by enhanced transcript levels of genes predicted to counteract alkylquinolone QS signals, respiratory toxins, and hydrogen cyanide.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The study showed <jats:italic>Mab<\/jats:italic> is capable of coexisting with <jats:italic>Pa<\/jats:italic> despite <jats:italic>Pa<\/jats:italic>\u2019s antagonistic effects, eliciting an adaptive molecular response in <jats:italic>Mab<\/jats:italic>. This study provides the first transcriptome-level insight into genetic interactions between the two CF pathogens offering potential strategies for disrupting their communities in a CF lung to improve patient clinical performance. Moreover, identification of a novel antimicrobial natural product with potent cidal activity against <jats:italic>Mab<\/jats:italic> could lead to new drug targets and therapies for Mab infections.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2025.1569331","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T05:34:20Z","timestamp":1746768860000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Mycobacterium abscessus persistence in the face of Pseudomonas aeruginosa antagonism"],"prefix":"10.3389","volume":"15","author":[{"given":"Rashmi","family":"Gupta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Schuster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle H.","family":"Rohde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1513\/AnnalsATS.201709-727OC","article-title":"Epidemiology of pulmonary nontuberculous mycobacterial sputum positivity in patients with cystic fibrosis in the United States, 2010-2014","volume":"15","author":"Adjemian","year":"2018","journal-title":"Ann. 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