Recebido em 29/6/05; aceito em 23/9/05; publicado na web em 31/3/06 RECENT ACHIEVEMENTS TO COMBAT BACTERIAL RESISTANCE. This article provides an overview on the recent achievements to combat Gram-positive bacteria and the mechanisms related to antimicrobial activity and bacterial resistance. Selected synthetic methodologies to access structurally diverse bioactive compounds are presented in order to emphasize the most important substances currently developed to overcome multiresistant strains. The main properties of vancomycin and related glycopeptide antibiotics are also discussed as a background to understanding the design of new chemotherapeutic agents.

Aspartic proteinases, which include HIV-1 proteinase, function with two aspartate carboxy groups at the active site. This relationship has been modeled in a system possessing an otherwise unactivated amide positioned between two carboxy groups. The model amide is cleaved at an enzyme-like rate that renders the amide nonisolable at 35 °C and pH 4 owing to the joint presence of carboxy and carboxylate groups. A currently advanced theory attributing almost the entire catalytic power of enzymes to electrostatic reorganization is shown to be superfluous when suitable interatomic interactions are present. Our kinetic results are consistent with spatiotemporal concepts where embedding the amide group between two carboxylic moieties in proper geometries, at distances less than the diameter of water, leads to enzyme-like rate enhancements. Space and time are the essence of enzyme catalysis.

Aspartic proteinases,w hich include HIV-1 proteinase,function with two aspartate carboxy groups at the active site.This relationship has been modeled in asystem possessing an otherwise unactivated amide positioned between two carboxyg roups.T he model amide is cleaved at an enzymelike rate that renders the amide nonisolable at 35 8 8Cand pH 4 owingtothe joint presence of carboxyand carboxylate groups. Ac urrently advanced theory attributing almost the entire catalytic power of enzymes to electrostatic reorganization is shown to be superfluous when suitable interatomic interactions are present. Our kinetic results are consistent with spatiotemporal concepts where embedding the amide group between two carboxylic moieties in proper geometries,atdistances less than the diameter of water,leads to enzyme-like rate enhancements. Space and time are the essence of enzyme catalysis.

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A reação da hidroxilamina com acetato de fenila foi investigada teoricamente para se obter uma melhor compreensão do efeito alfa nas reações de nucleófilos neutros. Os cálculos foram feitos em nível B3LYP/6-311+G(2df,2p)//HF/6-31G(d) incluindo o solvente (água) em nível PCM/HF/6-31G(d). Os resultados mostram que um ataque direto da hidroxilamina leva a uma barreira de energia livre de ativação DG ‡ muito alta, em torno de 50 kcal mol -1. Uma segunda molécula de hidroxilamina pode catalisar o processo através de catálise bifuncional usando ambos os grupos NH 2 e OH simultaneamente. Esta catálise bifuncional reduz o DG ‡ para 19 kcal mol -1 e é capaz de explicar a relação de produtos cinético e termodinâmico observada experimentalmente.The reaction of hydroxylamine with phenyl acetate was theoretically investigated to shed light on the role of catalysis and the origin of the a-effect in this system. Calculations at the B3LYP/6-311+G(2df,2p)//HF/6-31G(d) level and the solvent effect included at the PCM/HF/6-31G(d) level predict that the direct attack of hydroxylamine to the carbonyl centre has a high DG ‡ barrier, close to 50 kcal mol -1. A second hydroxylamine molecule can catalyse the process through bifunctional catalysis using both the NH 2 and OH groups simultaneously. This dual bifunctional catalysis decreases the DG ‡ to 19 kcal mol -1 and is able to explain the experimentally observed kinetics and product ratio.