Scalable and cost-effective tosylation-mediated synthesis of antifungal and fungal diagnostic 6″-Modified amphiphilic kanamycins.

Amphiphilic kanamycins bearing hydrophobic modifications at the 6″ position have attracted interest due to remarkable antibacterial-to-antifungal switches in bioactivity. In this report, we investigate a hurdle that hinders practical applications of these amphiphilic kanamycins: a cost-effective synthesis that allows the incorporation of various connecting functionalities to which the hydrophobic moieties are connected to the kanamycin core. A cost-effective tosylation enables various modifications at the 6″ position, which is scalable to a 90-g scale. The connecting functionalities, such as amine and thiol, were not the dominant factor for biological activity. Instead, the linear chain length played the decisive role. Amphiphilic kanamycin attached with tetradecyl (C14) or hexadecyl (C16) showed strong antifungal and modest antibacterial activities than with shorter chains (C6-C10). However, increases in chain length were closely correlated with an increase in HeLa cell toxicity. Thus, a compromise between the antimicrobial activities and cytotoxicities, for optimal efficacy of amphiphilic kanamycins may contain chain lengths between C8 and C12. Finally, the described synthetic protocol also allows the preparation of a fluorescent amphiphilic kanamycin selective toward fungi.

Development of Fungal Selective Amphiphilic Kanamycin: Cost-Effective Synthesis and Use of Fluorescent Analogs for Mode of Action Investigation.

Amphiphilic aminoglycosides have attracted interest due to their novel antifungal activities. A crucial but often neglected factor for drug development in academia is cost of production. Herein is reported a one-step, inexpensive synthesis of amphiphilic alkyl kanamycins constituted with only natural components. The synthetic methodology also enabled the preparation of a series fluorescent amphiphilic aryl kanamycins for direct structure-activity mode of action studies. The lead compounds showed prominent antifungal activities against a panel of fungi, including Fusarium graminearum, Cryptococcus neoformans, and several Candida sp., and also significant antibacterial activities. With fluorescence-based whole cell assays, the aryl amphiphilic kanamycins were observed to permeabilize fungal surface membranes at faster rates than bacterial surface membranes. Also, the antifungal action of the amphiphilic kanamycins was observed to occur in a biphasic mode with an initial fast phase correlated with rapid membrane permeabilization at subminimal inhibitory concentrations and a slower phase membrane permeabilization that elevates the reactive oxygen species production leading to cell death. Inactive hydrophobic amphiphilic kanamycins displayed no membrane permeabilization. The results offer cost-effective methods for producing amphiphilic kanamycins and reveal insights into how nonfungal specific amphiphilic kanamycins can be employed for fungal specific diagnostic and therapeutic applications.

Cost-effectiveness of management strategies for acute urethritis in the developing world.

OBJECTIVE: To recommend a cost-effective approach for the management of acute male urethritis in the developing world, based on the findings of a theoretical study. METHODS: A model was developed to assess the cost-effectiveness of three urethritis management strategies in a theoretical cohort of 1000 men with urethral syndrome. (1) All patients were treated with cefixime and doxycycline for gonococcal urethritis (GU) and nongonococcal urethritis (NGU), respectively, as recommended by WHO. (2) All patients were treated with doxycycline for NGU; treatment with cefixime was based on the result of direct microscopy of a urethral smear. (3) All patients were treated with cotrimoxazole or kanamycin for GU and doxycycline for NGU. Cefixime was kept for patients not responding to the first GU treatment. Strategy costs included consultations, laboratory diagnosis (where applicable) and drugs. The outcome was the rate of patients cured of urethritis. Cost-effectiveness was measured in terms of cost per cured urethritis. RESULTS: Strategy costs in our model depended largely on drug costs. The first strategy was confirmed as the most effective but also the most expensive approach. Cefixime should cost no more than US$ 1.5 for the strategy to be the most cost-effective. The second strategy saved money and drugs but proved a valuable alternative only when laboratory performance was optimal. The third strategy with cotrimoxazole was the least expensive but a low follow-up visit rate, poor treatment compliance or lower drug efficacy limited effectiveness. Maximizing compliance by replacing cotrimoxazole with single-dose kanamycin had the single greatest impact on the effectiveness of the third strategy. CONCLUSION: Our model suggested that a cost-effective approach would be to treat gonorrhoea with a single-dose antibiotic selected from locally available products that cost no more than US$ 1.5.