Surface-Shaving Proteomics of Mycobacterium marinum Identifies Biofilm Subtype-Specific Changes Affecting Virulence, Tolerance, and Persistence

Savijoki, Kirsi; Myllymäki, Henna; Luukinen, Hanna; Paulamäki, Lauri; Vanha-aho, Leena-Maija; Svorjova, Aleksandra; Miettinen, Ilkka T.; Fallarero, Adyary; Ihalainen, Teemu O.; Yli‐Kauhaluoma, Jari; Nyman, Tuula A.; Parikka, Mataleena

doi:10.1128/msystems.00500-21

Cited by 10 publications

(22 citation statements)

References 94 publications

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“…The minimum duration for killing (MDK) assay was performed as previously described [48]. Briefly, F0804-1219 and F1092-1799 were dissolved in dimethyl sulfoxide (Sigma Aldrich, St. Louis, MO) prior to being added on top of the Mmr biofilm cultures at the desired concentrations (8 µl/well).…”

Section: Minimum Duration For Killing (Bioluminescence)mentioning

confidence: 99%

WITHDRAWN: Mechanistic modeling of Mycobacterium tuberculosis β-carbonic anhydrase inhibitors using integrated systems biology and the QSAR approach

Bhowmik,

Manaithiya,

Parkkinen

et al. 2024

Preprint

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Mycobacterium tuberculosis (Mtb) β-carbonic anhydrases (β-CAs) are crucial enzymes responsible for regulating pH by catalyzing the conversion of CO2 to HCO3-, which is essential for its survival in acidic environments in the host. By inhibiting Mtb β-CAs, we can potentially discover new targets for anti-tuberculosis drugs with a different mechanism of action than existing FDA-approved drugs. This is crucial since Mtb has demonstrated the ability to develop different degrees of resistance to current drugs over time. This study employed machine learning-assisted quantitative structural activity relationship (ML-QSAR) models utilizing PubChem fingerprints, substructure fingerprints, and 1D 2D molecular descriptors to decipher the structural insights underlying the Mtb β-CA inhibition mechanism among 267 molecules. The final models, based on a random forest (RF) ML algorithm, demonstrated robustness with correlation coefficients of 0.931, 0.9227, and 0.9447, respectively. The final predictive models were further developed as a user-friendly web application, Mtb-CA-pred (https://mtb-ca-pred.streamlit.app/), which was further used to screen an anti-TB compound library of 11,800 molecules. We obtained two lead molecules, F0804-1219 and F1092-1799, from the virtual screening study, which were further subjected to a mechanistic systems biology framework to elucidate their inhibition mechanism through different biological pathways against Mtb β-CAs. Experimental validation via the minimum duration for killing (MDK) assay confirmed the bactericidal effects of the two identified compounds against Mycobacterium marinum biofilms, aligning computational predictions with experimental outcomes in drug discovery. These findings underscore the efficacy of the identified compounds as potent anti-TB agents, bridging computational and experimental approaches in anti-TB drug development.

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Section: Minimum Duration For Killing (Bioluminescence)mentioning

confidence: 99%

WITHDRAWN: Mechanistic modeling of Mycobacterium tuberculosis β-carbonic anhydrase inhibitors using integrated systems biology and the QSAR approach

Bhowmik,

Manaithiya,

Parkkinen

et al. 2024

Preprint

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“…demonstrated that the administration of nebulized cellulase enhanced the antimycobacterial activity of isoniazid and rifampicin in infected mice, supporting the role of biofilms in phenotypic drug tolerance ( Chakraborty et al., 2021 ). Savijoki et al. (2021) also reported that increased celA1 synthesis in M. marinum prevents biofilm formation and leads to reduced rifampicin tolerance.…”

Section: Discussionmentioning

confidence: 93%

mbtD and celA1 association with ethambutol resistance in Mycobacterium tuberculosis: A multiomics analysis

Tan²,

Zhang

et al. 2022

Front. Cell. Infect. Microbiol.

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Ethambutol (EMB) is a first-line antituberculosis drug currently being used clinically to treat tuberculosis. Mutations in the embCAB operon are responsible for EMB resistance. However, the discrepancies between genotypic and phenotypic EMB resistance have attracted much attention. We induced EMB resistance in Mycobacterium tuberculosis in vitro and used an integrated genome–methylome–transcriptome–proteome approach to study the microevolutionary mechanism of EMB resistance. We identified 509 aberrantly methylated genes (313 hypermethylated genes and 196 hypomethylated genes). Moreover, some hypermethylated and hypomethylated genes were identified using RNA-seq profiling. Correlation analysis revealed that the differential methylation of genes was negatively correlated with transcription levels in EMB-resistant strains. Additionally, two hypermethylated candidate genes (mbtD and celA1) were screened by iTRAQ-based quantitative proteomics analysis, verified by qPCR, and corresponded with DNA methylation differences. This is the first report that identifies EMB resistance-related genes in laboratory-induced mono-EMB-resistant M. tuberculosis using multi-omics profiling. Understanding the epigenetic features associated with EMB resistance may provide new insights into the underlying molecular mechanisms.

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“…Cording in vitro is typically studied using mycobacterial biofilms grown as pellicles at the air–liquid interface; an exception is cording described in rotary cell culture [ 43 ]. In contrast to pellicle biofilms, submerged mycobacterial biofilms have a non-corded, lichen-like morphology [ 39 ]. Cording occurs intracellularly (i.e., within the host) and is thought to impair host immune surveillance [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Mucispirillum schaedleri: Biofilm Architecture and Age-Dependent Pleomorphy

Desjardins,

Zerfas,

Filion

et al. 2023

Microorganisms

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Round bodies in spirochete cultures have been a controversial subject since their description seven decades ago. We report the existence of round bodies (spherical cells) in cultures of Mucispirillum schaedleri, a spiral bacterium phylogenetically distant from spirochetes. Furthermore, when grown in biofilms, M. schaedleri demonstrates a unique morphology known as cording, which has been previously described only in mycobacteria. Thus, M. schaedleri has two distinct features, each previously thought to be unique to two different phylogenetically distant groups of bacteria.

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Surface-Shaving Proteomics of Mycobacterium marinum Identifies Biofilm Subtype-Specific Changes Affecting Virulence, Tolerance, and Persistence

Cited by 10 publications

References 94 publications

WITHDRAWN: Mechanistic modeling of Mycobacterium tuberculosis β-carbonic anhydrase inhibitors using integrated systems biology and the QSAR approach

WITHDRAWN: Mechanistic modeling of Mycobacterium tuberculosis β-carbonic anhydrase inhibitors using integrated systems biology and the QSAR approach

mbtD and celA1 association with ethambutol resistance in Mycobacterium tuberculosis: A multiomics analysis

Mucispirillum schaedleri: Biofilm Architecture and Age-Dependent Pleomorphy

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