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M&Ms | The dependence of bacterial growth phase on Mycobacterium-Macrophage interaction

C M Bento(1,2) G S Oliveira(1,3) L Geerts(1,4) M S Gomes(1,3) T Silva(1,3)

1:i3S – Instituto de Investigação e Inovação e Saúde, Universidade do Porto; 2:MCBiology - Programa Doutoral em Biologia Molecular e Celular, Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto; 3:ICBAS – Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto; 4:University of Antwerp

Current treatments for nontuberculous mycobacterial infections rely on toxic multi-drug regimens, leading to low patient compliance and success rates. Consequently, there is an urgent need to develop more effective drugs. However, traditional methods used in anti-mycobacterial drug screening do not capture the complexity of these infections, thus failing at predicting clinical effectiveness.

When screening for drug activity against intramacrophagic bacteria, due to practicality and reproducibility issues, macrophages are often infected with frozen bacterial stocks. However, this is far from the in vivo conditions.

We assessed whether the liquid growth phase of Mycobacterium avium and M. abscessus (lag, exponential or stationary) upon infection impacted the host-pathogen interaction and, consequently, the infection outcome. Our results show that, depending on the growth phase, each species has differing intracellular growth and, most importantly, susceptibility to antibiotics. These differences are related to changes in macrophage vesicular trafficking, observed by monitoring the autophagic flux and lysosomal accumulation using live cell imaging.

We are further characterising the macrophage phenotype (e.g., cytokines profile) and performing transcriptomic analysis of the various mycobacterial growth phases to understand the reasons behind the different infection outcomes.

Choosing the right in vitro conditions for screening new compounds against mycobacteria is crucial to increasing assay predictability, which contributes to the success of drug discovery. Our findings emphasise the need to carefully choose these conditions, enabling the most effective and accurate screening process.

This work was financed by Portuguese national funds through Fundação para a Ciência e a Tecnologia, within the project PTDC/BIA-MIC/3458/2020.

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