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New Class of Antimicrobials Kills Multidrug-Resistant TB in 15 Minutes

Resistance to bisphosphocins appears to be impossible, company says

A recent series of in vitro studies have shown that bisphosphocins –– a novel class of antimicrobials –– are effective at killing multidrug-resistant (MDR) strains of Mycobacterium tuberculosis, the bacterium responsible for tuberculosis (TB). Approximately one-third of the world’s population is infected by this bacterium, which is increasingly becoming resistant to the current five-drug cocktail used to treat TB.

The new studies expand on previously published research, which demonstrated that the bisphosphocin Nu-3 could kill MDR bacteria. Specifically, time-kill studies showed that Nu-3 was highly effective, generating a 100% kill rate against MDR-TB strains CSU 39 and CSU 41 –– both of which are resistant to more than six classes of antibiotics –– and the wild-type strain H37Rv with as little as a 15-minute incubation period.

According to Lakewood-Amedex Inc., the developer of Nu-3, the mechanism of action of the bisphosphocin class is time- and concentration-dependent, resulting in the killing of both gram-positive and gram-negative bacteria in less time than they take to replicate.

In previously conducted investigations, Nu-3 eradicated a Pseudomonal lung infection with a single aerosolized dose. This result was significant, Lakewood-Amedex says, because bisphosphocins can eradicate both slow-growing and stationary bacteria, such as Mycobacterium, thereby eliminating any opportunity for the development of resistance. Based on these data, an aerosolized solo Nu-3 treatment would be expected to reduce the current five-drug TB treatment regimen, which is administered for up to 6 months or longer if the strains are found to be MDR-TB or extensively drug-resistant.

Four new antibiotics classes have recently been brought into clinical use: cyclic lipopeptides, such as daptomycin (Cubicin, Cubist); glycylcyclines, such as tigecycline (Tygacil, Pfizer); oxazolidinones, such as linezolid (Zyvox, Pfizer); and lipiarmycins, such as fidaxomicin (Dificid, Optimer/Cubist). While the discovery of these new antibiotic classes has provided physicians with the means to fight infections that are resistant to older antibiotics, these advantages may be offset by safety concerns. For example, daptomycin was originally discovered by Eli Lilly in the late 1980s, but further development was temporarily shelved because of the drug’s adverse effects on skeletal muscle, including myalgia and potential myositis. In addition, daptomycin resistance is already emerging worldwide, with cases reported in the U.S. as far back as 2007.

According to Lakewood-Amedex, most of the conventional antibiotics are bacteriostatic, requiring a properly functioning immune system to combat the infection. This limits treatment options in immunocompromised patients, such as those receiving chemotherapy or those with human immunodeficiency virus (HIV) infection. The few drugs that are bactericidal, such as the beta-lactam antibiotics (including the penams, cephems, and monobactams) as well as vancomycin, act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. This mechanism, however, requires the bacteria to attempt to replicate (divide) to be effective.

Bisphosphocins, on the other hand, bind directly to the membrane layer of bacterial (prokaryotic) cell walls, disrupting the membrane and causing depolarization and cell death. They are classified as low-toxicity or nontoxic substances.

“In contrast to traditional antibiotics, it appears impossible for bacteria to evolve resistance against the bisphosphocin class since initial testing has failed to identify or generate resistant bacterial strains,” Lakewood-Amedex says.

The company is developing Nu-3 as an intravenous formulation for serious bacterial infections, such as complicated urinary tract infections, and as a topical formulation for difficult-to-treat infections, such as chronic infected diabetic foot ulcers, fungal infections, and ophthalmic infections, where a broad spectrum of activity is required.

Sources: PipelineReview; May 19, 2015; and Lakewood-Amedex, Inc.; 2014.


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