Multidrug resistance to all existing classes of antibiotics, including those only recently approved for clinical use, is dirt common in nature.
That's the conclusion reached by a group of scientists from McMaster University in Ontario, Canada, in the Jan. 20, 2006, issue of Science.
The authors screened 480 strains of Streptomyces, a bacterium that synthesizes more than half of all known antibiotics, against high concentrations of 21 different clinically used antibiotics. They reported that "without exception, every strain in the library was found to be multidrug resistant to seven or eight antibiotics on average, with two strains being resistant to 15 of 21 drugs."
At first blush, the findings sound rather alarming. But Jeff Alder, vice president of drug discovery and evaluation at Lexington, Mass.-based Cubist Pharmaceuticals Inc., which provided part of the funding for the Science study, insists that the take-home news is positive.
For one thing, while most hospital bugs develop resistance through mutations in their genome that changes the target of an antibiotic beyond recognition, a different mechanism also was very common in the bacteria studied by the McMaster team: Bacteria had evolved enzymes that were able to disable six different antibiotics the scientists screened them against.
Alder said those enzymes mean that the soil probably holds many more clinically useful antibacterials that have been discovered to date. He told BioWorld Today that "there may be lots of yet undiscovered drugs in dirt that we're just not seeing" with current screening methods, because by the time the bacteria are screened, they have long since destroyed the antibiotic.
And resistance in the soil does not necessarily mean resistance in hospitals. One example is Cubist's Cubicin (daptomycin) which is highly active against a range of Gram-positive bacteria in the clinic. But it was "almost universally ineffective" against the soil bacteria screened by the McMaster team. Cubicin was approved for the treatment of skin and skin-structure infections cause by several different bacteria in 2003, and Cubist filed a supplemental NDA for bloodstream and known or suspected heart infections in 2005. (See BioWorld Today, Sept. 16, 2003, and June 29, 2005.)
The McMaster scientists noted in their paper that the soil could be "an under-recognized reservoir for resistance that has already emerged or has the potential to emerge in clinically important bacteria." Alder agreed that's the case for some antibiotics, but said daptomycin, and other antibiotics that are purely used in the clinic, are probably not among them. He said that Cubist had not seen any indication that resistance to daptomycin would be an unusually severe problem in a hospital setting, though more than 100,000 patients have been treated with the drug to date.
Alder said the transfer of resistance from the environment to the hospital is mainly a concern for antibiotics that are used agriculturally, in farm animals and for crop control. For such drugs, "there can be a much more direct link from gut flora in a pig to the pork chop on your table to the human gut," and from there into a hospital. But daptomycin is not used agriculturally, so there is no obvious path from soil to hospital.
"The two never come into contact in the first place," he said.
Alder also said that it is unsurprising that the Streptomyces bacteria used in the paper would be so resistant to antibiotics, including daptomycin, because they themselves manufacture them in nature: "One would not be surprised that the bug is resistant to the antibiotics it makes itself."
The study's first author, McMaster graduate student Vanessa D'Costa, concurred that the widespread resistance is unsurprising. Soil bacteria "live in an environment of antibiotic production," she told BioWorld Today.
Competition for real estate is fierce in the soil, and so bacteria secrete antibiotics to protect themselves against encroaching neighbors. That's the reason that soil bacteria also have evolved resistance mechanisms to the toxins secreted by their neighbors.
The findings also "don't necessarily give you a direct link" to suggest that the opposite resistance transfer pathway, from hospital overuse to soil resistance, is the major cause of resistance in soil bacteria, D'Costa said. Indeed, several newer antibiotics besides daptomycin encountered the stiffest bacterial resistance.
In a similar vein, the only universally effective antibiotic the scientists found was a Methuselah: neomycin. D'Costa said that finding was "very unexpected," - neomycin was discovered in 1949 and has been in clinical use for more than 50 years - but also cautioned that it's probably not a good idea to pin hopes on neomycin as the gatekeeper against a superbug epidemic.
For one thing, the scientists screened using high doses of antibiotics, so bacteria resistant to low levels of neomycin - or any other antibiotic - would not have come to their attention. For another, she said that "we screen one particular stage of the bacterial lifecycle." So the finding "could potentially be a function of the screen itself."