Antibiotic resistance and virulence of pathogenic mycobacteria are phenotypically associated, but the underlying genetic linkage has not been known. Here we show that PknG, a eukaryotic-type protein kinase previously found to support survival of mycobacteria in host cells, is required for the intrinsic resistance of mycobacterial species to multiple antibiotics.
SummaryThe MtrAB signal transduction system, which participates in multiple cellular processes related to growth and cell wall homeostasis, is the only two-component system known to be essential in Mycobacterium. In a screen for antibiotic resistance determinants in Mycobacterium smegmatis, we identified a multidrugsensitive mutant with a transposon insertion in lpqB, the gene located immediately downstream of mtrAmtrB. The lpqB mutant exhibited increased cell-cell aggregation and severe defects in surface motility and biofilm growth. lpqB cells displayed hyphal growth and polyploidism, reminiscent of the morphology of Streptomyces, a related group of filamentous Actinobacteria. Heterologous expression of M. tuberculosis LpqB restored wild-type characteristics to the lpqB mutant. LpqB interacts with the extracellular domain of MtrB, and influences MtrA phosphorylation and promoter activity of dnaA, an MtrA-regulated gene that affects cell division. Furthermore, in trans expression of the non-phosphorylated, inactive form of MtrA in wild-type M. smegmatis resulted in phenotypes similar to those of lpqB deletion, whereas expression of the constitutively active form of MtrA restored wild-type characteristics to the lpqB mutant. These results support a model in which LpqB, MtrB and MtrA form a three-component system that co-ordinates cytokinetic and cell wall homeostatic processes.
Objectives: Few studies have evaluated the long-term complications and
outcomes of esophageal atresia with or without tracheoesophageal fistula (EA/TEF)
beyond childhood. The aim of our study was to characterize the esophageal and
respiratory morbidity of EA/TEF through evaluation of clinical symptoms, diagnostic
testing and therapeutic intervention at a tertiary care center.Methods: Patients with congenital EA/TEF evaluated from 2011 to 2014
were included. Demographic characteristics, type and mode of repair of EA/TEF,
clinical symptoms, radiographic, endoscopic, bronchoscopic and medication use data
were obtained.Results: A total of 43 patients were identified. The median age of this
predominantly Caucasian population was 8 years (interquartile range: 3, 20). Twenty
(62.5%) had type C (EA with distal TEF) abnormality. Twenty-one (48.8%)
patients had heartburn, 19 (44.1%) had acid regurgitation, and 31
(72.1%) had dysphagia to solids. Barium swallow in 26 patients revealed
strictures in 17 (65.4%), dysmotility in 20 (76.9%) and recurrent
fistulas in four patients (15.4%). Thirty patients underwent upper endoscopy,
of which 21 (70.0%) had a stricture, and six (20.0%) had recurrent
fistula requiring surgical intervention. Eight (18.6%) patients underwent
fundoplication. Pulmonary evaluation showed cough and choking in 31 (72.1%)
patients and dyspnea and wheezing in 32 (53.4%) patients. Recurrent
respiratory infections were reported in 19 (44.2%).patients. Other findings
included tracheomalacia in 86.7% and restrictive lung disease in 54.5%
of patients.Conclusion: There is a high burden of residual esophageal and pulmonary
pathology in patients with EA/TEF. Ongoing follow-up is required to monitor both the
clinical symptoms and treatment responses.
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