The intracellular potassium (K(+) ) homeostasis, which is crucial for plant survival in saline environments, is modulated by K(+) channels and transporters. Some members of the high-affinity K(+) transporter (HAK) family are believed to function in the regulation of plant salt tolerance, but the physiological mechanisms remain unclear. Here, we report a significant inducement of OsHAK21 expression by high-salinity treatment and provide genetic evidence of the involvement of OsHAK21 in rice salt tolerance. Disruption of OsHAK21 rendered plants sensitive to salt stress. Compared with the wild type, oshak21 accumulated less K(+) and considerably more Na(+) in both shoots and roots, and had a significantly lower K(+) net uptake rate but higher Na(+) uptake rate. Our analyses of subcellular localizations and expression patterns showed that OsHAK21 was localized in the plasma membrane and expressed in xylem parenchyma and individual endodermal cells (putative passage cells). Further functional characterizations of OsHAK21 in K(+) uptake-deficient yeast and Arabidopsis revealed that OsHAK21 possesses K(+) transporter activity. These results demonstrate that OsHAK21 may mediate K(+) absorption by the plasma membrane and play crucial roles in the maintenance of the Na(+) /K(+) homeostasis in rice under salt stress.

We report novel polymyxin analogues with improved antibacterial in vitro potency against polymyxin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.

The plant Shaker K + channel AtAKT2 has been identified as a weakly rectifying channel that can stabilize membrane potentials to promote photoassimilate phloem loading and translocation. Thus, studies on functional characterization and regulatory mechanisms of AtAKT2-like channels in crops are highly important for improving crop production. Here, we identified the rice OsAKT2 as the ortholog of Arabidopsis AtAKT2, which is primarily expressed in the shoot phloem and localized at the plasma membrane. Using an electrophysiological assay, we found that OsAKT2 operated as a weakly rectifying K + channel, preventing H + /sucrose-symport-induced membrane depolarization. Three critical amino acid residues (K193, N206, and S326) are essential to the phosphorylation-mediated gating change of OsAKT2, consistent with the roles of the corresponding sites in AtAKT2. Disruption of OsAKT2 results in delayed growth of rice seedlings under short-day conditions. Interestingly, the lipid second messenger phosphatidic acid (PA) inhibits OsAKT2-mediated currents (both instantaneous and time-dependent components). Lipid dot-blot assay and liposomeprotein binding analysis revealed that PA directly bound with two adjacent arginine residues in the ANK domain of OsAKT2, which is essential to PA-mediated inhibition of OsAKT2. Electrophysiological and phenotypic analyses also showed the PA-mediated inhibition of AtAKT2 and the negative correlation between intrinsic PA level and Arabidopsis growth, suggesting that PA may inhibit AKT2 function to affect plant growth and development. Our results functionally characterize the Shaker K + channel OsAKT2 and reveal a direct link between phospholipid signaling and plant K + channel modulation.

Maintaining Na + /K + homeostasis is a critical feature for plant survival under salt stress, which depends on the operation of Na + and K + transporters. Although some K + transporters mediating root K + uptake have been reported to be essential to the maintenance of Na + /K + homeostasis, the effect of K + long-distance translocation via phloem on plant salt tolerance remains unclear. Here, we provide physiological and genetic evidence of the involvement of phloem-localized OsAKT2 in rice salt tolerance. OsAKT2 is a K + channel permeable to K + but not to Na + . Under salt stress, a T-DNA knock-out mutant, osakt2 and two CRISPR lines showed a more sensitive phenotype and higher Na + accumulation than wild type. They also contained more K + in shoots but less K + in roots, showing higher Na + /K + ratios. Disruption of OsAKT2 decreases K + concentration in phloem sap and inhibits shoot-to-root redistribution of K + . In addition, OsAKT2 also regulates the translocation of K + and sucrose from old leaves to young leaves, and affects grain shape and yield. These results indicate that OsAKT2-mediated K + redistribution from shoots to roots contributes to maintenance of Na + /K + homeostasis and inhibition of root Na + uptake, providing novel insights into the roles of K + transporters in plant salt tolerance.

Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.