A synthetic antibiotic class overcoming bacterial multidrug resistance.

The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern1. For more than five decades, the search for new antibiotics has relied heavily on the chemical modification of natural products (semisynthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semisynthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings2. Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, which we name iboxamycin. Iboxamycin is effective against ESKAPE pathogens including strains expressing Erm and Cfr ribosomal RNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native bacterial ribosome, as well as with the Erm-methylated ribosome, uncover the structural basis for this enhanced activity, including a displacement of the [Formula: see text] nucleotide upon antibiotic binding. Iboxamycin is orally bioavailable, safe and effective in treating both Gram-positive and Gram-negative bacterial infections in mice, attesting to the capacity for chemical synthesis to provide new antibiotics in an era of increasing resistance.

Tetracyclines promote survival and fitness in mitochondrial disease models.

Mitochondrial diseases (MDs) are a heterogeneous group of disorders resulting from mutations in nuclear or mitochondrial DNA genes encoding mitochondrial proteins1,2. MDs cause pathologies with severe tissue damage and ultimately death3,4. There are no cures for MDs and current treatments are only palliative5-7. Here we show that tetracyclines improve fitness of cultured MD cells and ameliorate disease in a mouse model of Leigh syndrome. To identify small molecules that prevent cellular damage and death under nutrient stress conditions, we conduct a chemical high-throughput screen with cells carrying human MD mutations and discover a series of antibiotics that maintain survival of various MD cells. We subsequently show that a sub-library of tetracycline analogues, including doxycycline, rescues cell death and inflammatory signatures in mutant cells through partial and selective inhibition of mitochondrial translation, resulting in an ATF4-independent mitohormetic response. Doxycycline treatment strongly promotes fitness and survival of Ndufs4-/- mice, a preclinical Leigh syndrome mouse model8. A proteomic analysis of brain tissue reveals that doxycycline treatment largely prevents neuronal death and the accumulation of neuroimmune and inflammatory proteins in Ndufs4-/- mice, indicating a potential causal role for these proteins in the brain pathology. Our findings suggest that tetracyclines deserve further evaluation as potential drugs for the treatment of MDs.

Residual feed intake phenotype and gender affect the expression of key genes of the lipogenesis pathway in subcutaneous adipose tissue of beef cattle.

BACKGROUND: Feed accounts for up to 75% of costs in beef production systems, thus any improvement in feed efficiency (FE) will benefit the profitability of this enterprise. Residual feed intake (RFI) is a measure of FE that is independent of level of production. Adipose tissue (AT) is a major endocrine organ and the primary metabolic energy reservoir. It modulates a variety of processes related to FE such as lipid metabolism and glucose homeostasis and thus measures of inter-animal variation in adiposity are frequently included in the calculation of the RFI index. The aim of this study was to determine the effect of phenotypic RFI status and gender on the expression of key candidate genes related to processes involved in energy metabolism within AT. Dry matter intake (DMI) and average daily gain (ADG) were measured over a period of 70 d for 52 purebred Simmental heifers (n = 24) and bulls (n = 28) with an initial BW±SD of 372±39.6 kg and 387±50.6 kg, respectively. Residual feed intake was calculated and animals were ranked within gender by RFI into high (inefficient; n = 9 heifers and n = 8 bulls) and low (efficient; n = 9 heifers and n = 8 bulls) groups. RESULTS: Average daily gain ±SD and daily DMI ±SD for heifers and bulls were 1.2±0.4 kg and 9.1±0.5 kg, and 1.8±0.3 kg and 9.5±1 kg respectively. High RFI heifers and bulls consumed 10% and 15% more (P < 0.05) than their low RFI counterparts, respectively. Heifers had a higher expression of all genes measured than bulls (P < 0.05). A gender × RFI interaction was detected for HMGCS2(P < 0.05) in which high RFI bulls tended to have lower expression of HMGCS2 than low RFI bulls (P < 0.1), whereas high RFI heifers had higher expression than low RFI heifers (P < 0.05) and high RFI bulls (P < 0.05). SLC2A4 expression was consistently higher in subcutaneous AT of low RFI animals across gender. CONCLUSION: The findings of this study indicate that low RFI cattle exhibit upregulation of the molecular mechanisms governing glucose metabolism in adipose tissue, in particular, glucose clearance. The decreased expression of SLC2A4 in the inefficient cattle may result in less efficient glucose metabolism in these animals. We conclude that SLC2A4 may be a potential biomarker for RFI in cattle.