Collateral Sensitivity to ß-Lactam Drugs in Drug-Resistant Tuberculosis Is Driven by the Transcriptional Wiring of BlaI Operon Genes.

The evolution of resistance to one antimicrobial can result in enhanced sensitivity to another, known as "collateral sensitivity." This underexplored phenomenon opens new therapeutic possibilities for patients infected with pathogens unresponsive to classical treatments. Intrinsic resistance to ß-lactams in Mycobacterium tuberculosis (the causative agent of tuberculosis) has traditionally curtailed the use of these low-cost and easy-to-administer drugs for tuberculosis treatment. Recently, ß-lactam sensitivity has been reported in strains resistant to classical tuberculosis therapy, resurging the interest in ß-lactams for tuberculosis. However, a lack of understanding of the molecular underpinnings of this sensitivity has delayed exploration in the clinic. We performed gene expression and network analyses and in silico knockout simulations of genes associated with ß-lactam sensitivity and genes associated with resistance to classical tuberculosis drugs to investigate regulatory interactions and identify key gene mediators. We found activation of the key inhibitor of ß-lactam resistance, blaI, following classical drug treatment as well as transcriptional links between genes associated with ß-lactam sensitivity and those associated with resistance to classical treatment, suggesting that regulatory links might explain collateral sensitivity to ß-lactams. Our results support M. tuberculosis ß-lactam sensitivity as a collateral consequence of the evolution of resistance to classical tuberculosis drugs, mediated through changes to transcriptional regulation. These findings support continued exploration of ß-lactams for the treatment of patients infected with tuberculosis strains resistant to classical therapies. IMPORTANCE Tuberculosis remains a significant cause of global mortality, with strains resistant to classical drug treatment considered a major health concern by the World Health Organization. Challenging treatment regimens and difficulty accessing drugs in low-income communities have led to a high prevalence of strains resistant to multiple drugs, making the development of alternative therapies a priority. Although Mycobacterium tuberculosis is naturally resistant to ß-lactam drugs, previous studies have shown sensitivity in strains resistant to classical drug treatment, but we currently lack understanding of the molecular underpinnings behind this phenomenon. We found that genes involved in ß-lactam susceptibility are activated after classical drug treatment resulting from tight regulatory links with genes involved in drug resistance. Our study supports the hypothesis that ß-lactam susceptibility observed in drug-resistant strains results from the underlying regulatory network of M. tuberculosis, supporting further exploration of the use of ß-lactams for tuberculosis treatment.

An anemia of Alzheimer's disease.

Lower hemoglobin is associated with cognitive impairment and Alzheimer's disease (AD). Since brain iron homeostasis is perturbed in AD, we investigated whether this is peripherally reflected in the hematological and related blood chemistry values from the Australian Imaging Biomarker and Lifestyle (AIBL) study (a community-based, cross-sectional cohort comprising 768 healthy controls (HC), 133 participants with mild cognitive impairment (MCI) and 211 participants with AD). We found that individuals with AD had significantly lower hemoglobin, mean cell hemoglobin concentrations, packed cell volume and higher erythrocyte sedimentation rates (adjusted for age, gender, APOE-ɛ4 and site). In AD, plasma iron, transferrin, transferrin saturation and red cell folate levels exhibited a significant distortion of their customary relationship to hemoglobin levels. There was a strong association between anemia and AD (adjusted odds ratio (OR)=2.43, confidence interval (CI) (1.31, 4.54)). Moreover, AD emerged as a strong risk factor for anemia on step-down regression, even when controlling for all other available explanations for anemia (adjusted OR=3.41, 95% CI (1.68, 6.92)). These data indicated that AD is complicated by anemia, which may itself contribute to cognitive decline.

Associations between gonadotropins, testosterone and ß amyloid in men at risk of Alzheimer's disease.

Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of ß amyloid (Aß) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Aß levels have focused primarily on plasma Aß(1-40) and not on the more pathogenic Aß(1-42). Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Aß levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Aß(1-40) and Aß(1-42) levels (beta=0.163, P<0.001; beta=0.446, P<0.001). This held in subjective memory complainers (SMC) (Aß(1-40); beta=0.208, P=0.017; Aß(1-42); beta=0.215, P=0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-ɛ4 allele (beta=0.536, P<0.001) and increasing serum LH levels (beta=0.421, P=0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-ɛ4 allele copy number (beta=0.674, P<0.001) and decreasing calculated free testosterone (beta=-0.303, P=0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease.

A blood-based predictor for neocortical Aß burden in Alzheimer's disease: results from the AIBL study.

Dementia is a global epidemic with Alzheimer's disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Aß (extracellular ß-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification. These scans are expensive and are not widely available, thus, there is a need for cheaper and more widely accessible alternatives. Addressing this need, a blood biomarker-based signature having efficacy for the prediction of NAB and which can be easily adapted for population screening is described. Blood data (176 analytes measured in plasma) and Pittsburgh Compound B (PiB)-PET measurements from 273 participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised. Univariate analysis was conducted to assess the difference of plasma measures between high and low NAB groups, and cross-validated machine-learning models were generated for predicting NAB. These models were applied to 817 non-imaged AIBL subjects and 82 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) for validation. Five analytes showed significant difference between subjects with high compared to low NAB. A machine-learning model (based on nine markers) achieved sensitivity and specificity of 80 and 82%, respectively, for predicting NAB. Validation using the ADNI cohort yielded similar results (sensitivity 79% and specificity 76%). These results show that a panel of blood-based biomarkers is able to accurately predict NAB, supporting the hypothesis for a relationship between a blood-based signature and Aß accumulation, therefore, providing a platform for developing a population-based screen.