A promising candidate drug for treating tuberculosis (TB), called SQ109 and undergoing phase 2 clinical trials, acts against Mycobacterium tuberculosis as well as other microbial pathogens and parasites via several different mechanisms, according to Eric Oldfıeld at the University of Illinois, Urbana-Champaign, and his collaborators. Not only SQ109, but also a series of analogues inhibit the growth of a range of microorganisms, acting at various molecular targets—leading to “very low rates of spontaneous drug resistance,” they report. “There’s an urgent need for new drugs that are resistance- resistant, and drugs that hit multiple targets will reduce resistance,” Oldfıeld adds. Details appeared February 25, 2014 in the Journal of Medicinal Chemistry (doi:10.1021/jm500131s).
SQ109 is a 1,2-diamine that is related to ethambutol, a widely used drug that is bacteriostatic against M. tuberculosis, blocking cell-wall production. Sequella, Inc. in Rockville, Md., a company focused on TB, began developing SQ109 in 2000, then in partnership with researchers at the National Institutes of Health (NIH) in nearby Bethesda, Md. Several years ago, members of the NIH group and their collaborators reported that SQ109 “interferes with the assembly of mycolic acids into the cell wall core of M. tuberculosis.” They also concluded that the primary bacterial target for the drug was MmpL3, “a transporter of trehalose monomycolate,” an ingredient of the cell wall in M. tuberculosis.
That seeming clarity for how SQ109 and analogues like it work, however, proved to be less than complete. Other researcher groups reported that SQ109 acts against other microbial species, including Helicobacter pylori bacteria and Candida albicans, a yeast. Neither one of them produces the MmpL3 transporter or makes cell walls like those of M. tuberculosis. Those and other results suggest that there must be other cellular targets for SQ109 and its analogues.
Oldfıeld and his collaborators tested SQ109 and a series of analogues against a battery of fıve bacteria, including M. tuberculosis, M. smegmatis, Staphylococcus aureus, Bacillus subtilis, and Escherichia coli, the two yeasts Saccharomyces cerevisiae and Candida albicans, and the malaria parasitePlasmodiumfalciparum. They also subjected human cells (cell line MCF-7) to those compounds to gauge their relative toxicities.
Two of the analogues are 4 to 5 times more potent than is SQ109 against M. tuberculosis in vitro, and one of them is 4 times less toxic against the human cell line. The compounds show varied activity against the other bacteria, yeasts, and P. falciparum—in general, targeting several different enzymes, including ones involved in menaquinone biosynthesis, electron transport, and inhibition of ATP biosynthesis.
“SQ109 and related compounds may be acting by a combination of mutually reinforcing mechanisms,” says Julio Urbina, emeritus investigator at the Venezuelan Institute for Scientifıc Research, near San Antonio de los Altos in Altos de Pipe, Miranda State. “This may explain their potency and suggests that they could represent a novel class of broad-spectrum anti-infective drugs, active against bacterial, fungal, and protozoan pathogens.”
“I hope the pharmaceutical industry, which has shown a distressing lack of interest in the discovery of antibiotics, will be stimulated by work like Oldfıeld’s,” says Andrew McCammon, a Howard Hughes Medical Institute Investigator and distinguished professor of pharmacology at the University of California, San Diego. Another plus, he adds, is that these antibiotic candidates have “the remarkable property of inhibiting not just one, but several essential cellular functions in pathogenic bacteria, fungi, and the malaria parasite.” Such antimicrobial products, if used clinically, thus might be less prone to stimulating the development of drug resistance in pathogens.
Carol Potera is a freelance writer in Great Falls, Mont.