抗菌素耐药性的长期难题之一是为什么耐药性的频率持续在中等水平。缺乏抵抗力的理论解释包括抵抗力的隐秘成本或负频率依赖性,但很少进行实验研究。β-内酰胺酶,可以解毒青霉素相关的抗生素,具有由作弊和合作驱动的特征良好的频率相关动态。然而,细菌生理学决定了β-内酰胺酶是否合作,我们对β-内酰胺酶生产者在感染中的社会性或适应性知之甚少。此外,基于媒体的实验限制了我们如何测量健康,忽略了重要的参数,如传染性和宿主之间的传播。这里,我们调查了广谱AmpCβ-内酰胺酶在阴沟肠杆菌肉汤中的适应性影响,生物膜,和模型昆虫的肠道感染。我们使用头孢噻肟量化了频率和剂量依赖性适合度,第三代头孢菌素.我们预测感染动力学将与生物膜中观察到的相似,社会保护范围很广。我们发现了β-内酰胺酶在所有情况下具有负频率依赖性选择的社会性的证据,确保野生型细菌的持久性,尽管合作在生物膜中不那么普遍,与预测相反。虽然肠道感染和肉汤中的竞争适应性具有相似的动力学,将传染性纳入感染适应性的测量中会显著影响结论。抗性细菌的感染性降低,这限制了对低抗生素剂量和低初始耐药频率挑战的感染的抵抗力的健康益处。抗性细菌在更生理耐受状态下的适应性(在生物膜中,在感染中)可能受到野生型细菌的存在的限制,高抗生素剂量,和有限的β-内酰胺酶的可用性。一个结论是增加β-内酰胺的耐受性不一定增加抗性的选择压力。总的来说,在这项研究中,隐秘的健身成本和频率依赖性都降低了抵抗带来的健身益处.
One of the longstanding puzzles of antimicrobial resistance is why the frequency of resistance persists at intermediate levels. Theoretical explanations for the lack of fixation of resistance include cryptic costs of resistance or negative frequency-dependence but are seldom explored experimentally. β-lactamases, which detoxify penicillin-related antibiotics, have well-characterized frequency-dependent dynamics driven by cheating and
cooperation. However, bacterial physiology determines whether β-lactamases are cooperative, and we know little about the sociality or fitness of β-lactamase producers in infections. Moreover, media-based experiments constrain how we measure fitness and ignore important parameters such as infectivity and transmission among hosts. Here, we investigated the fitness effects of broad-spectrum AmpC β-lactamases in Enterobacter cloacae in broth, biofilms, and gut infections in a model insect. We quantified frequency- and dose-dependent fitness using cefotaxime, a third-generation cephalosporin. We predicted that infection dynamics would be similar to those observed in biofilms, with social protection extending over a wide dose range. We found evidence for the sociality of β-lactamases in all contexts with negative frequency-dependent selection, ensuring the persistence of wild-type bacteria, although
cooperation was less prevalent in biofilms, contrary to predictions. While competitive fitness in gut infections and broth had similar dynamics, incorporating infectivity into measurements of fitness in infections significantly affected conclusions. Resistant bacteria had reduced infectivity, which limited the fitness benefits of resistance to infections challenged with low antibiotic doses and low initial frequencies of resistance. The fitness of resistant bacteria in more physiologically tolerant states (in biofilms, in infections) could be constrained by the presence of wild-type bacteria, high antibiotic doses, and limited availability of β-lactamases. One conclusion is that increased tolerance of β-lactams does not necessarily increase selection pressure for resistance. Overall, both cryptic fitness costs and frequency dependence curtailed the fitness benefits of resistance in this study.