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Aromatic dicationic molecules possess impressive activity against a broad spectrum of microbial pathogens, including Pneumocystis carinii, Cryptosporidium parvum, and Candida albicans. In this work, 58 aromatic cations were examined for inhibitory activity against axenic amastigote-like Leishmania donovani parasites. In general, the most potent of the compounds were substituted diphenyl furan and thiophene dications. 2,5-Bis-(4-amidinophenyl)thiophene was the most active compound. This agent displayed a 50% inhibitory concentration (IC 50 ) of 0.42 ؎ 0.08 M against L. donovani and an in vitro antileishmanial potency 6.2-fold greater than that of the clinical antileishmanial dication pentamidine and was 155-fold more toxic to the parasites than to a mouse macrophage cell line. 2,4-Bis-(4-amidinopheny)furan was twice as active as pentamidine (IC 50 , 1.30 ؎ 0.21 M), while 2,5-bis-(4-amidinopheny)furan and pentamidine were essentially equipotent in our in vitro antileishmanial assay. Carbazoles, dibenzofurans, dibenzothiophenes, and benzimidazoles containing amidine or substituted amidine groups were generally less active than the diphenyl furans and thiophenes. In all cases, aromatic dications possessing strong antileishmanial activity were severalfold more toxic to the parasites than to a cultured mouse macrophage cell line. These structure-activity relationships demonstrate the potent antileishmanial activity of several aromatic dications and provide valuable information for the future design and synthesis of more potent antiparasitic agents.

Methionine aminopeptidase 2 (MetAP2) is responsible for the hydrolysis of the initiator methionine molecule from the majority of newly synthesized proteins. We have cloned the MetAP2 gene from the malaria parasite Plasmodium falciparum (PfMetAP2; GenBank accession number AF348320). The cloned PfMetAP2 has no intron, consists of 1,544 bp and encodes a protein of 354 amino acids with a molecular mass of 40,537 D and an overall base composition of 72.54% A + T. PfMetAP2 has 40% sequence identity with human MetAP2 and 45% identity with yeast MetAP2, and is located in chromosome 14 of P. falciparum. The three-dimensional structure of Pf MetAP2 has been modeled based on the crystal structure of human MetAP2, and several amino acid side chains protruding into the binding pocket that differ between the plasmodial and human enzyme have been identified. The specific MetAP2 inhibitors, fumagillin and TNP-470, potently blocked in vitro growth of P. falciparum and Leishmania donavani, with IC(50) values similar to the prototype drugs. Furthermore, in the case of P. falciparum, the chloroquine-resistant strains are equally susceptible to these two compounds.

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The deoxyribonucleic acids (DNA) from phenotypically unusual Leptospira strains were compared to each other and to reference strains of existing genetic groups. In the "pathogenic" genetic complex, three groups emerged as genetically distinct. Representative examples of these groups were bataviae strain Van Tienen, javanica strain Veldrat Bataviae, and ranarum strain Iowa City Frog. The serologically different muenchen strain Muenchen 90C, icterohaemorrhagiae strain RGA, and kabura strain Kabura were found to be closely related to bataviae strain Van Tienen. The "saprophytic"genetic complex also contained three inter-related groups. The representative examples were patoc strain Patoc I, codice strain CDC, and Turtle strain A-183. Strain 3055 of serotype illini appeared t o have unique nucleotide sequences and was placed in a third genetic complex of its own. Partial relatedness between DNA could be emphasized by increasing the salt concentrations in the incubation media. This could not be attributed t o the methods of annealing but appeared to be dependent upon the genetic relatedness between the heterologous DNA.The genus Leptospira can be separated into two major divisions, the pathogenic and the so-called "sap rop hy t icy' or "bifle xa " lep t 0-spiras. The latter are usually found in fresh surface waters and are rarely found in animals. In addition to infectivity, various phenotypic properties serve to separate members of the two divisions (1 8). Using deoxyribonucleic acid (DNA) base composition determinations and specific DNA-DNA annealing tests in agar matrices, Haapala et al. (7) demonstrated genetic differences between, as well as within, serotypes in the two divisions. Two distinct genetic groups were demonstrated among selected strains within each of the pathogenic and biflexa serotypes. The serological relationships among lep tospiras did not necessarily denote genetic relatedness; however, strains of the same or very similar serotypes appeared to be in the same genetic group. The two genetic groups of pathogenic lep tospiras could be differentiated from each other and from the two biflexa groups by a number of phenotypic characteristics which also served as a basis for the leptospiral groups described by Johnson and Harris (9). The principal differentiating attributes were lipase production and relative resistance to the bacteriostatic action of 8-azaguanine (AZA) and 2,6-diaminopurine (DAP).The genetic groups of pathogenic strains represented by strains of serotypes bataviae and javanica corresponded to the Johnson and Harris biological groups 1 and 2, respectively. Group 1 strains were sensitive to AZA and DAP and had lipase activity, whereas group 2 strains were sensitive to AZA, resistant t o DAP, and lacked lipase activity. The two genetic groups of biflexa strains were phenotypically indistinguishable and fit into the Johnson and Harris biological group 3 , which was characterized by resistance to both purine analogues and by positive lipase activity.