NEWS OF THE WEEK
DRUG CONJUGATE NABS HIDDEN STAPH BIOTECHNOLOGY: Antibody-antibiotic
duo targets Staphylococcus aureus surviving inside host cells
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HEN STAPHYLOCOCCUS AUREUS sneaks
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into our bodies, it usually lives outside of our cells. But sometimes the microbes invade cells, possibly to hide out and survive antibiotic treatment—leading to persistent or relapsing infections. Genentech researchers have now developed an antibody-antibiotic conjugate, or AAC, that targets S. aureus taking refuge in host cells. Preclinical tests show that AACs are more MRSA effective than standard treatments for clearing S. aureus infections in O mice (Nature 2015, DOI: S 10.1038/nature16057). N In past decades, researchO ers had reported evidence that successful human pathogens tend to escape into host cells, says Sanjeev Mariathasan, who led S. aureus antibody the Genentech team. “So the question was: ‘How do we kill these pathogens? Is that the reason we have these repeated infections?’ ” To start answering those questions, Genentech scientists first confirmed that these host cell reservoirs pose a significant problem by comparing mice infected with either free methicillin-resistant S. aureus (MRSA) or MRSA sequestered inside mouse immune cells. After four days without any treatment, many mice receiving
the sequestered MRSA had higher bacterial burdens. Also, standard MRSA treatments were unable to eliminate the sequestered bacteria. The scientists created an anti-S. aureus antibody that binds to certain sugars on the surface of the bacteria. They attached a rifamycin-derived antibiotic called rifalogue to unpaired cysteines on the antibody with a linker molecule. Hundreds of these AACs can attach to the surface of a bacterium before it invades a host’s immune cell. Once there, intracellular proteases cleave the linker and release the AAC’s antibiotic cargo. The AAC “turns the pathogen into a Trojan horse,” says Kim Lewis, director of the Antimicrobial Discovery Center at Northeastern University. “The antibiotic is released to kill both the incoming bacteria and those already present in mammalian cells.” S. aureus bacteria remain in a specific host cell for about two or three days before escaping into another. Mariathasan explains that the long half-life of the OH AACs allows them to latch onto bacteria throughout this process. “As long as these AACs are onboard in the patient,” he says, “they N
O N H
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OCH3 O
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OH O HO
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+ N
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CH3 CH3 Rifalogue
Linker NH
Inside of host cells, proteases cleave would then capture a linker on the antibody-antibiotic these bacteria and NH2 O conjugate, releasing rifalogue molecules eventually put an end (one shown here) and killing bacteria. to the vicious cycle.” (Model not to scale.) In mice with systemic MRSA infections, the researchers found that one dose of AAC was able to clear the bacteria within 24 hours, beating out standard vancomycin treatments. Genentech currently has a patent on the technology, and Mariathasan says the group is “serious” about exploring the strategy in humans.—JUDITH LAVELLE
CONSUMER PRODUCTS Environmental group launches safe cosmetics verification program The Environmental Working Group, an activist organization, has launched a verification seal for personal care products intended to help consumers avoid toxic chemicals and contaminants that it says are commonly found in cosmetics. The seal, known as EWG Verified, will make shopping “easier for overwhelmed consumers who want to quickly find a bottle of shampoo or a tube of toothpaste that is better for their health,” says Ken Cook, the group’s president. Two small cosmetic makers, Beautycounter and MyChelle Dermaceuticals, will be the first program participants.
Products eligible for the mark cannot contain probable reproductive, carcinogenic, or environment-damaging toxins, EWG says. Among the ingredients the group proscribes are paraben preservatives and nitro- and polycyclic musk fragrance ingredients, all of which it considers suspected endocrine disruptors. However, personal care products that include synthetic chemicals aren’t automatically barred from receiving the EWG seal. Although sunscreen formulas aren’t covered in the new verification program, the group has argued in favor of certain synthetic sunscreen ingredients permit-
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ted in Europe but not allowed in the U.S. Seal-eligible products must also meet other criteria such as scoring high in EWG’s Skin Deep cosmetics database and fully disclosing ingredients on packaging labels. Only products that “meet our robust criteria, as opposed to minimal government standards,” are eligible to receive the mark, says Nneka Leiba, the group’s deputy director of research. Leiba says she hopes the program will spur development of safer products. If successful, the group plans to roll out the program to other goods it tracks such as cleaners and food.—MARC REISCH
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