In vitro activities of 2,2'-bipyridyl analogs against Mycobacterium leprae

Abstract

In vitro susceptibility ofMycobacterium leprae to two bipyridyl analogs was studied by using two biochemical parameters to measure the metabolic activity of the organism. VUF-8514 at 0.16 ,uglml, but not VUF-8842, completely inhibited the metabolic activity of M. keprae, and the action was bactericidal. When compared to rifampin (MIC 0.3 ,ug/ml), VUF-8514 was equally bactericidal against M. keprae. The aim of the present study was to evaluate the activities of these analogs, in comparison to that of rifampin, against M. leprae in an in vitro culture system. Antimicrobial agents. The 2,2'-bipyridyl analogs, VUF-8514 (isoquinoline derivative) and VUF-8842 (1,10-phenanthroline derivative) were obtained from H. Timmerman of Free University, Amsterdam, The Netherlands. The structural formulae and chemistry of these compounds have been described earlier (3)(4)(5) (7). ATP determinations were carried out by the firefly bioluminescent technique described earlier (8), while the procedure of Khanolkar and coworkers (17) was followed for the measurement of thymidine uptake.The effect of drug on M. leprae in primary culture was evaluated after incubating cultures for 4 weeks at 34°C. To determine if the effects were bacteriostatic or bactericidal, the cells from 4-week-old primary cultures were washed twice with fresh DH medium and then suspended in fresh DH medium without the drug and incubated at 34°C for four more weeks. At this time, ATP and [3H]thymidine uptake assays were again performed.Sampling for the assays from primary and subcultures was done as described previously. The results presented here were derived from three separate experiments, using different M. leprae strain in each experiment. In each experiment, triplicate assays were done for each concentration of every drug including rifampin.Susceptibility of M. leprae to bipyridyls. In the control cultures (without drugs), metabolic activity of M. leprae in primary cultures at 4 weeks was 143% of that at zero hour (Table 1). When the cells from these primary cultures were transferred to fresh DH medium, the activity in subcultures was 134% of the original at zero hour of these subcultures (143% increase in primary cultures was adjusted to 100% at zero hour for subcultures). With VUF-8514 at concentrations of 0.08 ,ug/ml and below, the metabolic activity of M. keprae in primary cultures as well as in subcultures was the same in control cultures. However, when the concentration of VUF-8514 in primary cultures was 0.16 ,ug/ml and higher, no metabolic activity could be detected, suggesting the MIC of VUF-8514 against M. leprae was 0.16 ,ug/ml. When these cells from primary cultures were transferred to fresh drug-free DH medium, cells failed to exhibit any metabolic activity, even after 4 weeks. This suggests the bactericidal activity of VUF-8514 on M leprae. On the other hand, VUF-8842 had no inhibitory effect on the metabolic activity of M leprae even at 0.32 ,ug/ml-the highest concentration tested to compare against rifampin, whose MIC against M leprae has been ...

Inhibition of growth of Histoplasma capsulatum yeast cells in human macrophages by the iron chelator VUF 8514 and comparison of VUF 8514 with deferoxamine

“…When tested in axenic culture medium, this compound was reported to inhibit the growth of several microorganisms such as Mycoplasma spp. (12), Candida albicans (41), and Escherichia coli (41), as well as mycobacterial species including Mycobacterium tuberculosis (13), Mycobacterium avium (13), and Mycobacterium leprae (14). However, further studies on the pharmacology and toxicology of VUF 8514 will be required to determine its potential usefulness in the treatment of infectious diseases.…”

DNA and RNA Synthesis: Antifolates

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“…108 Epiroprim is also synergistic with dapsone against Mycobacterium leprae in vivo. 109 To the best of our knowledge, there is no development work ongoing with this compound. Pyrimethamine/Dapsone (Maloprim).…”

Thioridazine: resurrection as an antimicrobial agent?

“…In vitro experiments using THP‐1 macrophage cell lines and human peripheral monocyte‐derived macrophages infected with M. tuberculosis have shown that the minimum bactericidal concentration of thioridazine is as low as 0.1 mg l −1 , with complete killing occurring within 3 days of infection [29]. Phenothiazines affect a number of key mycobacterial targets [31–33]. They bind to and inactivate calmodulin, a calcium transport protein which is a vital constituent of the cell wall envelope of mycobacteria [34–36].…”