A library of 85000 microbial fermentation extracts was screened for inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa and Candida albicans. New compounds EA-371alpha and EA-371delta were isolated and demonstrated to be potent and specific inhibitors of the MexAB-OprM pump in P. aeruginosa. Two series of fungal metabolites, enniatins and beauvericins, were found to be ubiquitous and potent inhibitors of ABC transporters. Milbemycins were rediscovered as potent inhibitors of the CDRI pump in C. albicans, and demonstrated to potentiate effectively the antifungal activity of fluconazole and SCH-56592 against a wide variety of Candida clinical isolates.

ATP-Binding Cassette Transporters↗

PubMedDate not supplied

Experimental shock chemistry of aqueous amino acid solutions and the cometary delivery of prebiotic compounds.

A series of shock experiments were conducted to assess the feasibility of the delivery of organic compounds to the Earth via cometary impacts. Aqueous solutions containing near-saturation levels of amino acids (lysine, norvaline, aminobutyric acid, proline, and phenylalanine) were sealed inside stainless steel capsules and shocked by ballistic impact with a steel projectile plate accelerated along a 12-m-long gun barrel to velocities of 0.5-1.9 km sec-1. Pressure-temperature-time histories of the shocked fluids were calculated using 1D hydrodynamical simulations. Maximum conditions experienced by the solutions lasted 0.85-2.7 microseconds and ranged from 5.1-21 GPa and 412-870 K. Recovered sample capsules were milled open and liquid was extracted. Samples were analyzed using high performance liquid chromatography (HPLC) and mass spectrometry (MS). In all experiments, a large fraction of the amino acids survived. We observed differences in kinetic behavior and the degree of survivability among the amino acids. Aminobutyric acid appeared to be the least reactive, and phenylalanine appeared to be the most reactive of the amino acids. The impact process resulted in the formation of peptide bonds; new compounds included amino acid dimers and cyclic diketopiperazines. In our experiments, and in certain naturally occurring impacts, pressure has a greater influence than temperature in determining reaction pathways. Our results support the hypothesis that significant concentrations of organic material could survive a natural impact process.

Amino Acids↗

PubMedDate not supplied

Renal uptake and nephrotoxicity of gentamicin during urinary alkalinization in rats.

1. Effect of urine pH on accumulation of gentamicin in the renal cortex of rats was studied following constant intravenous infusion, and single or repeated i.v. injections with gentamicin. 2. The cortical uptake of gentamicin was moderately inhibited by urinary alkalinization due to sodium bicarbonate treatment, but was unaffected by acidification with ammonium chloride. The altered urinary pH had no effect on urinary excretion of gentamicin. 3. An alkaline urine induced by acetazolamide injections failed to influence cortical accumulation of gentamicin. This effect may be ascribed to 'acidification' of the proximal tubular fluid after carbonic anhydrase inhibition, even though the final urine was alkaline. 4. Nephrotoxicity resulting from chronic treatment of gentamicin was ameliorated by concomitant sodium bicarbonate administration. 5. In conclusion, the intratubular pH of the proximal tubule is a factor which influences the cortical uptake of gentamicin, probably by means of changing the cationic nature of the molecule and, therefore, reduced binding with the luminal membrane.

Animals↗

PubMedDate not supplied

Response to Dr. Waldron's critique of smoking studies.

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Adult↗

PubMedDate not supplied

What mathematics courses should an experimental biologist take?

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Biochemistry↗