Genome-wide mapping of fluoroquinolone-stabilized DNA gyrase cleavage sites displays drug specific effects that correlate with bacterial persistence.
Genome-wide mapping of fluoroquinolone-stabilized DNA gyrase cleavage sites displays drug specific effects that correlate with bacterial persistence.
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DOI：
10.1093/nar/gkac1223
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发表时间：
2023-02-22
影响因子：
14.9
通讯作者：
Brynildsen, Mark P.
中科院分区：
文献类型：
--
作者：
Tang, Juechun;Brynildsen, Mark P.
细菌持久性是罕见的表型变异，被怀疑是复发性感染的罪魁祸首。氟喹诺酮类（FQs）是一类抗生素，当它们与切割的DNA形成复合物时，通过稳定细菌II型拓扑异构酶来促进细菌杀伤。在大肠杆菌中，DNA促旋酶是FQ的主要靶标，并且先前的工作已经证明，持留菌不能幸免于大肠杆菌诱导的DNA损伤。由于DNA促旋酶切割位点（GCS）在很大程度上控制了FQ处理的DNA损伤位点，因此我们假设GCS特征（例如数量、强度、位置）可能影响持久性。为了验证这一假设，我们在稳定期培养物中用一组FQs处理后测量了全基因组GCS分布。我们发现药物对GCS分布的特异性影响，并发现基因组切割强度和FQ持久水平之间存在强烈的负相关性。进一步的实验和分析表明，持久性不太可能由切割到个别网站，而是生存是一个功能的基因组GCS分布。总之，这些研究结果表明GCS分布中与持久性水平相关的特定差异，并表明在与DNA的切割复合物中更好地稳定DNA促旋酶的FQs将导致较低水平的持久性。
Bacterial persisters are rare phenotypic variants that are suspected to be culprits of recurrent infections. Fluoroquinolones (FQs) are a class of antibiotics that facilitate bacterial killing by stabilizing bacterial type II topoisomerases when they are in a complex with cleaved DNA. In Escherichia coli, DNA gyrase is the primary FQ target, and previous work has demonstrated that persisters are not spared from FQ-induced DNA damage. Since DNA gyrase cleavage sites (GCSs) largely govern the sites of DNA damage from FQ treatment, we hypothesized that GCS characteristics (e.g. number, strength, location) may influence persistence. To test this hypothesis, we measured genome-wide GCS distributions after treatment with a panel of FQs in stationary-phase cultures. We found drug-specific effects on the GCS distribution and discovered a strong negative correlation between the genomic cleavage strength and FQ persister levels. Further experiments and analyses suggested that persistence was unlikely to be governed by cleavage to individual sites, but rather survival was a function of the genomic GCS distribution. Together, these findings demonstrate FQ-specific differences in GCS distribution that correlate with persister levels and suggest that FQs that better stabilize DNA gyrase in cleaved complexes with DNA will lead to lower levels of persistence.
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影响因子：
4.9
作者：
Bagel, S;Hüllen, V;Heisig, P
通讯作者：
Heisig, P
影响因子：
14.9
作者：
Gene Ontology Consortium
通讯作者：
Gene Ontology Consortium
DOI：
10.1073/pnas.83.15.5558
发表时间：
1986-08-01
影响因子：
11.1
作者：
AMUNDSEN, SK;TAYLOR, AF;SMITH, GR
通讯作者：
SMITH, GR
影响因子：
5.4
作者：
Allison, Kyle R.;Brynildsen, Mark P.;Collins, James J.
通讯作者：
Collins, James J.
Biopython：用于计算分子生物学和生物信息学的免费 Python 工具。
DOI：
10.1093/bioinformatics/btp163
发表时间：
2009-06-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Cock PJ;Antao T;Chang JT;Chapman BA;Cox CJ;Dalke A;Friedberg I;Hamelryck T;Kauff F;Wilczynski B;de Hoon MJ
通讯作者：
de Hoon MJ