Saebelfeld Manja, Das Suman G, Brink Jorn, Hagenbeek Arno, Krug Joachim, de Visser J Arjan G M
Institute for Biological Physics, University of Cologne, Cologne, Germany.
Laboratory of Genetics, Department of the Plant Sciences Group, Wageningen University and Research, Wageningen, Netherlands.
Front Microbiol. 2021 Aug 19;12:698970. doi: 10.3389/fmicb.2021.698970. eCollection 2021.
For a better understanding of the evolution of antibiotic resistance, it is imperative to study the factors that determine the initial establishment of mutant resistance alleles. In addition to the antibiotic concentration, the establishment of resistance alleles may be affected by interactions with the surrounding susceptible cells from which they derive, for instance the release of nutrients or removal of the antibiotic. Here, we investigate the effects of social interactions with surrounding susceptible cells on the establishment of mutants with increasing β-lactamase activity (i.e., the capacity to hydrolyze β-lactam antibiotics) from single cells under the exposure of the antibiotic cefotaxime (CTX) on agar plates. We find that relatively susceptible cells, expressing a β-lactamase with very low antibiotic-hydrolyzing activity, increase the probability of mutant cells to survive and outgrow into colonies due to the active breakdown of the antibiotic. However, the rate of breakdown by the susceptible strain is much higher than expected based on its low enzymatic activity. A detailed theoretical model suggests that this observation may be explained by cell filamentation causing delayed lysis. While susceptible cells may hamper the spread of higher-resistant β-lactamase mutants at relatively high frequencies, our findings show that they promote their initial establishment.
为了更好地理解抗生素耐药性的演变，研究决定突变耐药等位基因初始建立的因素至关重要。除了抗生素浓度外，耐药等位基因的建立可能会受到与它们所源自的周围敏感细胞相互作用的影响，例如营养物质的释放或抗生素的去除。在这里，我们研究了在琼脂平板上暴露于抗生素头孢噻肟（CTX）的情况下，与周围敏感细胞的社会相互作用对单细胞中β-内酰胺酶活性增加（即水解β-内酰胺抗生素的能力）的突变体建立的影响。我们发现，表达具有非常低抗生素水解活性的β-内酰胺酶的相对敏感细胞，由于抗生素的主动分解，增加了突变细胞存活并生长成菌落的概率。然而，敏感菌株的分解速率远高于基于其低酶活性所预期的速率。一个详细的理论模型表明，这一观察结果可能是由细胞丝状化导致的延迟裂解所解释的。虽然敏感细胞可能会在相对高频率下阻碍更高耐药性β-内酰胺酶突变体的传播，但我们的研究结果表明，它们促进了这些突变体的初始建立。
