Compensatory evolution of pbp mutations restores the fitness cost imposed by β-lactam resistance in Streptococcus pneumoniae.
Compensatory evolution of pbp mutations restores the fitness cost imposed by β-lactam resistance in Streptococcus pneumoniae.
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DOI：
10.1371/journal.ppat.1002000
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发表时间：
2011-02
期刊：
影响因子：
6.7
通讯作者：
Echenique J
中科院分区：
文献类型：
--
作者：
Albarracín Orio AG;Piñas GE;Cortes PR;Cian MB;Echenique J
病原菌中抗生素耐药基因的普遍存在是治疗许多传染病的一大挑战。这些基因的传播是由使用抗菌药物所施加的强选择所驱动的。然而，在没有药物选择的情况下，抗生素抗性基因强加了适应性成本，这可以通过补偿突变来改善。在肺炎链球菌中，β-内酰胺耐药性是由三种青霉素结合蛋白PBP 1a、PBP 2x和PBP 2b的突变引起的，所有这些蛋白都与细胞壁合成和细胞分裂周期有关。我们发现，健身成本和细胞分裂缺陷所赋予的pbp 2b突变（确定健身竞争性测定在体外和体内和荧光显微镜）完全补偿收购pbp 2x和pbp 1a突变，显然是通过增加稳定性和随之而来的这些蛋白质突变体的错误定位。因此，pbp突变等位基因的这些补偿性组合导致β-内酰胺抗性水平和谱的增加。这份报告描述了抗生素耐药性增加和健身成本补偿之间的直接相关性，两者都是由水平转移获得的相同基因突变引起的。pbp突变的临床起源表明，这种基因间补偿过程与循环菌株中β-内酰胺耐药的持续存在有关。我们认为这种代偿机制与肺炎链球菌β-内酰胺耐药的进化有关。多年来，肺炎球菌感染通常用β-内酰胺类药物治疗。然而，在过去的二十年中，β-内酰胺耐药性的迅速出现使这些感染的抗菌治疗变得复杂。抗生素耐药性的出现和稳定是一个复杂的生物学过程，由不同的因素驱动，例如抗生素的使用量。此外，许多关于减少β-内酰胺消耗的影响的研究报告了对S. pneumoniae，表明其他因素有助于β-内酰胺耐药性的持续存在。通过水平基因转移，S.肺炎克雷伯氏菌能够从耐药菌株或链球菌获得基因，这赋予β-内酰胺耐药性。在这里，我们表明，当某些抗性基因单独获得，一个重要的成本结果在细菌的健身。然而，一些获得增加β-内酰胺类耐药基因的临床菌株也可以补偿这种耐药所带来的适应性成本，从而产生选择优势并提高β-内酰胺类耐药的潜在传播。我们认为，pbp 1a和pbp 2x突变等位基因获得的补偿作用健身除了他们的贡献，在发展更高的β-内酰胺耐药水平，这一过程可能会发生，即使在没有抗生素。
The prevalence of antibiotic resistance genes in pathogenic bacteria is a major challenge to treating many infectious diseases. The spread of these genes is driven by the strong selection imposed by the use of antibacterial drugs. However, in the absence of drug selection, antibiotic resistance genes impose a fitness cost, which can be ameliorated by compensatory mutations. In Streptococcus pneumoniae, β-lactam resistance is caused by mutations in three penicillin-binding proteins, PBP1a, PBP2x, and PBP2b, all of which are implicated in cell wall synthesis and the cell division cycle. We found that the fitness cost and cell division defects conferred by pbp2b mutations (as determined by fitness competitive assays in vitro and in vivo and fluorescence microscopy) were fully compensated by the acquisition of pbp2x and pbp1a mutations, apparently by means of an increased stability and a consequent mislocalization of these protein mutants. Thus, these compensatory combinations of pbp mutant alleles resulted in an increase in the level and spectrum of β-lactam resistance. This report describes a direct correlation between antibiotic resistance increase and fitness cost compensation, both caused by the same gene mutations acquired by horizontal transfer. The clinical origin of the pbp mutations suggests that this intergenic compensatory process is involved in the persistence of β-lactam resistance among circulating strains. We propose that this compensatory mechanism is relevant for β-lactam resistance evolution in Streptococcus pneumoniae. For many years, pneumococcal infections have been usually treated with β-lactams. However, the rapid emergence of β-lactam resistance has complicated the antimicrobial treatment of these infections in the last two decades. The emergence and stability of antibiotic resistance is a complex biological process driven by different factors, such as the volume of antibiotic used. Furthermore, many studies on the effect of a reduction in β-lactam consumption have reported a sustained resistance level to S. pneumoniae, suggesting that other factors contribute to the persistence of β-lactam resistance. By horizontal gene transfer, S. pneumoniae is able to acquire genes from resistant strains or the commensal streptococci, which confer β-lactam resistance. Here, we show that when certain resistance genes are acquired individually, an important cost results in the bacterial fitness. However, some clinical strains which have acquired genes that increase β-lactam resistance can also compensate the fitness cost imposed by this resistance, thereby producing a selective advantage and raising the potential spreading of β-lactam resistance. We suggest that pbp1a and pbp2x mutant alleles are acquired for their compensatory effect on fitness in addition to their contribution in developing higher β-lactam resistance levels, and that this process may occur even in the absence of antibiotics.
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DOI：
10.1073/pnas.86.22.8842
发表时间：
1989-11-01
影响因子：
11.1
作者：
DOWSON, CG;HUTCHISON, A;SPRATT, BG
通讯作者：
SPRATT, BG
影响因子：
3.1
作者：
BRILES, DE;CRAIN, MJ;YOTHER, J
通讯作者：
YOTHER, J
DOI：
10.1007/bf02113426
发表时间：
1995-06-01
影响因子：
4.5
作者：
LEFEVRE, JC;BERTRAND, MA;FAUCON, G
通讯作者：
FAUCON, G
影响因子：
3.2
作者：
Di Guilmi, AM;Mouz, N;Vernet, T
通讯作者：
Vernet, T
影响因子：
3
作者：
Albarracin Orio, Andrea G.;Cortes, Paulo R.;Echenique, Jose R.
通讯作者：
Echenique, Jose R.