Antimicrobials: New and Old Molecules in the Fight Against Multi-resistant Bacteria

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Unfortunately, growing resistance is gradually rendering them ineffective, with the threat of catastrophic public health consequences should this trend continue much longer. The few new antibiotics being brought to market essentially consist of so-called me-too drugs -- meaning that they are derived from existing classes of antibiotics. What we had identified was a molecule with dual toxic and antibiotic properties.

We thought that if we could separate these activities, we would be able to create a new antibiotic non-toxic to the body.

Antibiotics: when bacteria fight back - News from the Institut Pasteur

A challenge that we accepted! As their name suggests, these peptides are inspired by the existing natural bacterial peptides but have been shortened and modified. Out of the twenty molecules created, two proved effective against resistant Staphylococcus aureus and Pseudomonas aeruginosa in mouse models of severe sepsis or skin infection.

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In addition, no toxicity to the other cells and organs, whether in animals or human cells was observed. These new compounds are well tolerated at their active doses -- and even beyond -- and are devoid of the renal toxicity issues often encountered with this type of compound. Important to note was that the bacteria that the researchers had left in contact for several days in the animals with these antibiotics showed no signs of resistance.

In order to go further, the researchers created conditions favorable to the development of resistance in vitro and in vivo -- with nothing happening. In closing, recently developed compounds already in clinical use, those in preclinical or first clinical studies, and a number of promising targets to be exploited in the discovery stage are discussed.

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Examines the latest developments in antibacterial research and drug design Integrates basic and clinical aspects Written by international experts see more benefits. Buy eBook. Sure enough, when treated with acpP-specific PPMOs, mice infected with multidrug-resistant Acinetobacter baumannii survived for at least one week, while control mice died, most within a day J Infectious Diseases , , Geller and the other researchers hope their work will one day bear fruit in the clinic, but for now, such new drugs emerging from old discoveries remain merely a preclinical glimmer of hope, with many years of work ahead before medicine gets a desperately needed novel class of antimicrobials.

Bayer Healthcare scientists discovered the drug in but later dropped it after in vitro experiments showed that bacteria rapidly developed resistance to it. But, like Sello, Lewis and his colleagues thought that it just needed a little help. So they combined ADEP4 with a conventional antibiotic, rifampicin, in the hopes that the treatment would be effective—and stay effective—against Staphylococcus aureus, which readily forms antibiotic-resistant biofilms harboring dormant cells known as persisters.

The therapy worked better than anyone had dared to hope: while ADEP4 and rifampicin each reduced microbial populations in vitro and in mice, administered together they obliterated the bacteria Nature , , Triggering ClpP to degrade proteins nonspecifically in persister cells within biofilms may have caused the breakdown of hundreds of proteins, forcing the cells to self-digest, Lewis says. Yanmin Hu, a medical microbiologist at St. Hu and Helperby founder Coates used high-throughput screening to identify HT61, a small antibiotic compound that exhibited selective bactericidal activity against methicillin-susceptible S.

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The result in vitro and in mouse models: HT61 enhances the antimicrobial activities of traditional antibiotics, especially aminoglycosides such as neomycin, gentamicin, and chlorhexidine, against MSSA and MRSA J Antimicrobial Chemother , , Hu says that the combination therapy likely worked so well—far better than either antibiotic administered alone—because HT61 was essentially punching holes in the membranes of nondividing bacterial cells, allowing the aminoglycosides to flood in.

Used as a topical agent in combination with the antibiotic mupirocin, HT61 has cleared Phase 1 and 2 trials for the treatment of latent MRSA infections, Hu says. She and Coates have also identified a plethora of other potential compounds that might serve to enhance the effects of existing antibiotics.

The idea of a magic bullet is gone. We need a magic shotgun.

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  • Antibiotics can also be combined with existing, nonantibiotic drugs, as Wright is doing. In , he and his colleagues screened more than 1, approved drugs for compounds that augmented the ability of the antibiotic minocycline to fight infection.

    New antibiotics effective without triggering resistance, mouse study shows

    Although adjuvants themselves are unable to kill bacteria, when added to antibiotic regimens they render resistant microbes susceptible once again. From a financial standpoint, antibiotic adjuvants make sense. Developing and validating a small-molecule sensitizer to be used in conjunction with an existing antibiotic should cost far less than developing and validating a completely new drug. The adjuvant allows one to shift that threshold.

    One way microbes are evolving resistance to first-line antibiotics is by blocking entry of the drug into the cell. For example, the Boston-based firm Collins cofounded, EnBiotix, is working on potentiators such as silver compounds that sensitize persistent bacteria to existing antibiotics by increasing bacterial membrane permeability.