Department of Zoology, University of Oxford, Oxford, OX1 3PS, UK.
Center for Disease Dynamics, Economics & Policy, New Delhi, 110020, India.
ISME J. 2018 Jun;12(6):1582-1593. doi: 10.1038/s41396-018-0090-4. Epub 2018 Mar 21.
Bacteria commonly live in dense and genetically diverse communities associated with surfaces. In these communities, competition for resources and space is intense, and yet we understand little of how this affects the spread of antibiotic-resistant strains. Here, we study interactions between antibiotic-resistant and susceptible strains using in vitro competition experiments in the opportunistic pathogen Pseudomonas aeruginosa and in silico simulations. Selection for intracellular resistance to streptomycin is very strong in colonies, such that resistance is favoured at very low antibiotic doses. In contrast, selection for extracellular resistance to carbenicillin is weak in colonies, and high doses of antibiotic are required to select for resistance. Manipulating the density and spatial structure of colonies reveals that this difference is partly explained by the fact that the local degradation of carbenicillin by β-lactamase-secreting cells protects neighbouring sensitive cells from carbenicillin. In addition, we discover a second unexpected effect: the inducible elongation of cells in response to carbenicillin allows sensitive cells to better compete for the rapidly growing colony edge. These combined effects mean that antibiotic treatment can select against antibiotic-resistant strains, raising the possibility of treatment regimes that suppress sensitive strains while limiting the rise of antibiotic resistance. We argue that the detailed study of bacterial interactions will be fundamental to understanding and overcoming antibiotic resistance.
细菌通常生活在与表面相关的密集且遗传多样的群落中。在这些群落中，资源和空间的竞争非常激烈，但我们对这如何影响抗生素耐药菌株的传播知之甚少。在这里，我们使用体外竞争实验和计算机模拟研究了机会性病原体铜绿假单胞菌中抗生素耐药和敏感菌株之间的相互作用。在群体中，细胞内对抗生素链霉素的抗性选择非常强烈，以至于在非常低的抗生素剂量下就有利于抗性。相比之下，群体中β-内酰胺酶分泌细胞对羧苄西林的细胞外抗性选择较弱，需要高剂量的抗生素才能选择抗性。操纵菌落的密度和空间结构表明，这种差异部分是由于β-内酰胺酶分泌细胞局部降解羧苄西林，从而保护邻近的敏感细胞免受羧苄西林的影响。此外，我们发现了第二个意外的效果：细胞对羧苄西林的感应伸长，使敏感细胞能够更好地在快速生长的菌落边缘竞争。这些综合效应意味着抗生素治疗可以选择对抗生素耐药菌株，从而有可能抑制敏感菌株的生长，同时限制抗生素耐药性的上升。我们认为，对细菌相互作用的详细研究将是理解和克服抗生素耐药性的基础。
