VOMG molecule effective against M. abscessus lung infections in CF
The bacteria has a natural resistance to many antibiotics now used in clinics
A new small molecule, called VOMG, showed good antimicrobial activity against Mycobacterium abscessus, a bacterium that can cause serious infections in people with cystic fibrosis (CF).
“The bactericidal and eradicating properties of VOMG … strongly reinforce the potential of VOMG in the treatment of pulmonary infections especially in CF individuals, even when the standard of care treatment is not effective,” the researchers wrote.
The study, “The novel drug candidate VOMG kills Mycobacterium abscessus and other pathogens by inhibiting cell division,” was published in the International Journal of Antimicrobial Agents.
CF is caused by mutations in the CFTR gene that lead to thick mucus accumulating in the lungs and other organs. As a result, bacteria and other germs can become trapped in the airways, making it harder to clear them out, which increases the risk of lung infections.
Especially because it has a natural resistance to many antibiotics used in clinics, M. abscessus, which grows rapidly, can cause serious lung infections in people with CF.
No antibiotics have been developed specifically for M. abscessus, so its treatment using a combination of old antibiotics has “very poor success rates,” the researchers wrote. “There is therefore a crucial need to develop new [M. abscessus-specific] drugs with a novel mechanism of action to be effective against these multidrug-resistant [bacteria].”
The FtsZ protein is crucial for bacterial multiplication and exists only in bacteria, making it a good therapeutic target for antibiotics with a broad spectrum of action. While some FtsZ suppressor molecules have shown some efficacy against M. abscessus in lab studies, “currently, there are no FtsZ inhibitors in the [M. abscessus] drug development pipeline,” the researchers wrote.
Potential new drug candidate for CF lung infections
Here, researchers in Italy identified a new small molecule, called VOMG, that demonstrated powerful activity against M. abscessus and other bacteria.
The researchers started by creating several small molecules derived from a class of molecules called pyridine 1-oxides, which are known for their properties against Mycobacterium tuberculosis, the most common cause of tuberculosis.
The molecules showed moderate efficacy in lab studies against M. abscessus at low concentrations. The researchers reasoned the molecules could act as a prodrug, an inactive compound that’s converted into an active agent once it’s in the body. In fact, they confirmed that one of these compounds, called x-VOMG, did act as a prodrug and was converted into an active agent, called VOMG, that exhibited higher antimicrobial activity against M. abscessus than x-VOMG.
The researchers then focused on VOMG alone. In time-kill assays, which assess the time it takes for an antimicrobial agent to kill a bacterial strain, VOMG’s efficacy was noticeable after 24 hours. It also had a sterilizing effect, meaning no bacterial growth was observed, after 14 days.
“This represents an improvement compared to most drugs used in [M. abscessus] therapy,” wrote the researchers, who tested other antibiotics and found they showed bactericidal activity at higher concentrations and were associated with a slower onset of activity and no sterilizing capacity.
VOMG also significantly prevented the formation of M. abscessus biofilms, that is, layers of microorganisms that stick together on wet surfaces as a protective mechanism, and reduced the thickness of mature biofilms.
This was an advantage over the antibiotics amikacin, which showed no activity against M. abscessus biofilms, and clarithromycin, which had no effect on mature biofilm thickness.
In a combination assay with nine therapies currently used against M. abscessus, VOMG showed no detrimental effects, “indicating the suitability of VOMG for combination therapy,” the researchers wrote.
VOMG also showed greater activity than x-VOMG against several other bacteria that cause lung infections in CF patients, including Mycobacterium avium and Staphylococcus aureus. But no activity was observed against Klebsiella pneumoniae and Pseudomonas aeruginosa, whose infections are a key contributor to lung disease in CF.
Mouse studies showed a single oral VOMG dose of 50 mg/kg was generally safe and had favorable pharmacokinetics, which is the movement into, through, and out of the body, with peak concentration achieved after four hours.
In mice infected with M. abscessus, intranasal administration of VOMG at 50 mg/kg significantly reduced the bacterial load in the lungs and bloodstream over untreated mice. VOMG also suppresses the multiplication processes in M. abscessus, particularly by targeting FtsZ, and in a dose-dependent manner, analyses showed.
The findings show “promise for a new drug candidate with the possibility to use different formulations in the much-needed and narrow [M. abscessus] drug development pipeline,” the researchers wrote. “Potential progression of VOMG into the clinic might bring new therapeutic options to treat lung disease caused by this [bacterium] and other susceptible microorganisms.”
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