Biology subjects

Tueffers, L.

Publications and source records attributed to Tueffers, L..

3 recordsLinked to original sources

bioRxiv2025

Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa via negative hysteresis in the cell envelope

Antibiotic combination in time and space is a key strategy to combat antimicrobial resistance. The success of such treatment designs requires their robust efficacy across treatment conditions and a pathogens genomic diversity. This study found that an initial treatment with a {beta}-lactam antibiotic causes robust cellular sensitization towards an aminoglycoside antibiotic across the high-risk human pathogen Pseudomonas aeruginosa, including resistant strains. This phenomenon of cellular sensitization, termed negative hysteresis, is modulated by the Cpx envelope stress response system and linked to membrane stress during growth. The increase in efficacy is achieved through a {beta}-lactam induced elevated cellular uptake of the subsequently administered aminoglycoside. Negative hysteresis and the Cpx system are linked in several cases to the expression of synergistic drug interactions, thus enhancing efficacy of antibiotic combinations. Overall, our study identifies the phenomenon of negative hysteresis as a robustly inducible phenotype and thus a unique focus for optimizing antimicrobial therapy.

evolutionary biology↗

bioRxiv2025

Resistance variation and bacterial interactions shape the adaptation of a genetically diverse bacterial population to antimicrobial treatment

Bacterial infections are often polymicrobial and subject to the evolution of antimicrobial resistance (AMR). Existing knowledge on AMR in such polymicrobial infections usually relies on observational patient data, for which cause-effect relationships are difficult to infer, or on studying interactions between different bacterial species, ignoring the commonly encountered variation within species. Here, we therefore asked how mixed populations with strains from the same species evolve under antibiotic treatment. We used a genetically diverse population of the high-risk human pathogen Pseudomonas aeruginosa, and first identified strain variation in both AMR and pairwise bacteria-bacteria interactions, the latter ranging from beneficial, neutral, to competitive. Using experimental evolution, we subsequently demonstrate that the response to selection by different antibiotic treatments is significantly influenced by AMR strain variation, bacterial interactions, and also spatial population structure. Moreover, de novo AMR evolution was additionally impacted by variation in resistance rates towards the two considered antibiotics. A second evolution experiment emphasized the central role of strain variation and bacterial interactions in determining the evolutionary outcome. We conclude that ecological dynamics in genetically diverse pathogen populations are key for our general understanding of infection characteristics and AMR evolution, and, therefore, deserve particular attention during treatment of polymicrobial infections.

evolutionary biology↗

bioRxiv2024

Variation in the response to antibiotics and life-history across the major Pseudomonas aeruginosa clone type (mPact) panel

Pseudomonas aeruginosa is a ubiquitous, opportunistic human pathogen. Since it often expresses multidrug resistance, it is ranked by the World Health Organization among the top 3 high priority pathogens, for which new treatment options are urgently required. An evaluation of new treatments is usually performed experimentally with one of the canonical laboratory strains (e.g., PAO1 or PA14). However, these two strains are unlikely representative of the strains infecting patients, because they have adapted to laboratory conditions and do not capture the enormous genomic diversity of the species. Here, we characterized the major P. aeruginosa clone type (mPact) panel. This panel consists of 20 strains, which reflect the genomic diversity of the species, cover all major clone types, and have both patient and environmental origins. We found significant strain variation in distinct responses towards antibiotics and general growth characteristics. Only few of the measured traits are related, and if so, only for specific antibiotics. Moreover, high levels of resistance were only identified for clinical mPact isolates and could be linked to known AMR (antimicrobial resistance) genes in the sequenced genomes. One strain also produced highly unstable AMR, indicating an evolutionary cost to resistance expression. By linking isolation source, growth, and virulence to life history traits, we further identified specific adaptive strategies for individual mPact strains towards either host processes or degradation pathways. Overall, the mPact panel provides a reasonably sized set of distinct strains, enabling in-depth analysis of new treatment designs or evolutionary dynamics in consideration of the species genomic diversity. ImportanceNew treatment strategies are urgently needed for high risk pathogens such as the opportunistic and often multidrug resistant pathogen Pseudomonas aeruginosa. Here, we characterize the major P. aeruginosa clone type (mPact) panel. It consists of 20 strains with different origins that cover the major clone types of the species as well as its genomic diversity. This mPact panel shows significant variation in (i) resistance against distinct antibiotics, including several last resort antibiotics, (ii) related traits associated with the response to antibiotics, and (iii) general growth characteristics. We further developed a novel approach that integrates information on resistance, growth, virulence, and life-history characteristics, allowing us to demonstrate the presence of distinct adaptive strategies of the strains that focus either on host interaction or resource processing. In conclusion, the mPact panel provides a manageable number of representative strains for this important pathogen for further in-depth analyses of treatment options and evolutionary dynamics.

microbiology↗