Opportunistic etiological agents causing lung infections: emerging need to transform lung-targeted delivery
A New Approach Can Address Antibiotic Resistance To Mycobacterium Abscessus
Scientists at St. Jude Children's Research Hospital are tackling Mycobacterium abscessus (Mab) antibiotic resistance. This naturally antibiotic-resistant pathogen is becoming more prevalent, highlighting the urgent need for novel therapeutics. To address this, the scientists designed new versions of the drug spectinomycin that overcome efflux, the main mechanism driving resistance. The work was published today in Proceedings of the National Academy of Science.
Mab infections are increasingly found in health care settings. Such infections can be hazardous for patients with compromised lung function, such as in cystic fibrosis, or who are immunologically compromised, such as in childhood cancer. These infections are treated with long courses of antibiotics and can result in poor outcomes. The emergence of Mab and other similar pathogens presents a growing and deeply concerning public health threat because there are few effective therapeutic options and a limited drug development pipeline.
"We chemists are in a race against the pathogens. We make stronger antibiotics, and the pathogens become more resistant," said corresponding author Richard Lee, PhD, St. Jude Department of Chemical Biology and Therapeutics.
Scientists at St. Jude modified the naturally occurring antibiotic spectinomycin to create analogs, comparable but structurally distinct N-ethylene linked aminomethyl spectinomycins (eAmSPCs). These synthetically created eAmSPCs are up to 64 times more potent against Mab than standard spectinomycin.
"By re-engineering the molecule through structure-based drug design, we and our collaborators have adapted the antibiotic to increase its activity," Lee added.
Overcoming efflux to make a more effective antibiotic
Through their work, the scientists unraveled the mechanism of action by which eAmSPCs are more effective: they circumvent efflux. Efflux is the process that cells use to get rid of a drug -- imagine pumping water out of a flooded basement -- and is a significant mechanism by which cells become resistant to therapy.
The N-ethylene linkage structure of the eAmSPCs plays a critical role in how the compounds avoid efflux, suggesting that longer linkages modify how the compound is pumped out of the cell. This ultimately shifts the balance toward higher concentrations of eAmSPC within the cell and thus enhances antimicrobial efficacy.
"Over the past two decades, we've seen a massive increase in the number of infections caused by non-tuberculous mycobacteria like Mab," said co-first author Gregory Phelps, PharmD, St. Jude Graduate School of Biomedical Sciences. "We had a place to start with this naturally occurring antibiotic, which, through modification, we've made much more efficacious against this clinically relevant pathogen."
The researchers also found that eAmSPCs work well with various classes of antibiotics used to treat Mab and retain their activity against other mycobacterial strains. Collectively, this work demonstrates that eAmSPCs should be further studied and developed because once issues of tolerability and safety are addressed, these compounds could become next-generation therapeutics.
"It is challenging to attract pharmaceutical companies to develop new antibiotics for several economic reasons," said Phelps. "If we can boost the drug pipeline against this hard-to-treat bacteria, we can potentially make a difference for patients like the ones we have here at St. Jude who are increasingly faced with limited or no therapeutic options."
New Rifamycin Drugs Fight Antibiotic-resistant Lung Infections More ...
Modified antibiotics beat a stubborn lung pathogen and dodge metabolic landmines, offering new hope for patients with HIV, cystic fibrosis, and TB co-infections.
Study: Next-generation rifamycins for the treatment of mycobacterial infections. Image Credit: Kateryna Kon / Shutterstock
The rise of drug-resistant bacteria is a major health crisis. Moreover, the development of antibiotic resistance in pulmonary pathogens such as Mycobacterium abscessus, against which treatment options are already limited, poses a serious problem for cystic fibrosis patients and immunocompromised individuals.
A recent study published in the Proceedings of the National Academy of Sciences explored new versions of rifamycins, antibiotics traditionally used to treat tuberculosis, to combat severe lung infections caused by M. Abscessus. The researchers also explored modifications to the drug that could boost its strength and reduce harmful interactions with other medications.
Treating Mycobacterium infectionsRifamycins are essential antibiotics, widely used to treat tuberculosis. These drugs effectively target and eliminate various mycobacterial populations. However, their effectiveness is limited against lung infections caused by M. Abscessus, a non-tuberculous Mycobacterium, as the bacterium has intrinsic resistance to many antibiotics.
Mycobacterium abscessus develops resistance through mechanisms that include drug inactivation. Rifamycins also carry the risk of negative interactions with other drugs by affecting liver enzymes. This is particularly problematic for patients with conditions like cystic fibrosis or human immunodeficiency virus (HIV), who require multiple medications. These concerns highlight the urgent need for new rifamycins that are more potent against M. Abscessus and have fewer drug interactions.
About the studyIn the present study, the researchers from the United States and Germany systematically identified and evaluated new rifamycin compounds through a multi-stage process. They began by synthesizing various analogs of the rifamycin antibiotic rifabutin and screening them for their ability to inhibit the growth of both wild-type M. Abscessus and a mutant strain lacking the enzyme adenosine diphosphate (ADP)-ribosyltransferase (Arr), which confers resistance to rifamycins.
This initial screen aimed to select compounds that could overcome the bacterium's intrinsic resistance mechanism. Compounds demonstrating favorable potency progressed to the next stage, where their plasma protein binding was assessed in human and mouse plasma.
The researchers then used mouse models to examine the compounds' pharmacokinetics, which is how the drugs move through the body, and their uptake by macrophages, a type of immune cell that engulfs bacteria in lung lesions. This helped predict how well the drugs would reach their target within infected tissues. Compounds with promising pharmacokinetic properties, comparable to or better than rifabutin, were chosen for further evaluation.
The selected compounds underwent additional biological profiling to thoroughly assess their effectiveness against M. Abscessus. This included evaluating their bactericidal activity against different forms of the bacteria, such as extracellular (outside cells), intracellular (inside cells), replicating, and nonreplicating. The activity against nonreplicating bacteria is particularly important because these bacteria can survive in a dormant state and are often resistant to antibiotics.
Furthermore, the potential for drug-drug interactions was investigated by measuring the induction of the cytochrome P450 3A4 (CYP3A4) enzyme in human hepatocytes. This enzyme is involved in metabolizing many drugs, and its induction can lead to reduced effectiveness or increased toxicity of other medications. Finally, the compounds' cytotoxicity, or their ability to harm human cells, was assessed to determine their safety profile.
Major findingsThe study found that several new rifamycin analogs, particularly the lead candidates UMN-120 and UMN-121, which belong to a C25-substituted carbamate series, exhibited significantly improved potency against M. Abscessus compared to the current drug, rifabutin. This enhanced activity was attributed to the strategic modification of these analogs to overcome the bacterium's intrinsic resistance mechanisms, specifically ADP-ribosylation.
The new compounds demonstrated potent bactericidal activity against both replicating and nonreplicating M. Abscessus, including intracellular bacteria residing within macrophages. This was particularly noteworthy since nonreplicating, drug-tolerant bacteria often contribute to the persistence of infection.
A key finding of the study was the reduced potential for drug-drug interactions with the new rifamycin analogs. Rifamycins, including rifabutin, can induce the CYP3A4 enzyme, which plays a critical role in metabolizing various drugs. Induction of CYP3A4 can lead to decreased effectiveness or increased toxicity of other medications. The researchers found that several of the new analogs, including the lead candidates, exhibited significantly lower CYP3A4 induction compared to rifabutin, suggesting a reduced risk of such interactions. Crucially, these compounds retained high potency against Mycobacterium tuberculosis, the cause of TB, meaning they could potentially treat TB without the drug interaction liability common to existing rifamycins, offering a significant advantage for patients co-infected with HIV.
Furthermore, in mouse models of M. Abscessus lung infection, the lead compounds UMN-120 and UMN-121 demonstrated remarkable efficacy. When administered as single agents, they were shown to be at least as effective in reducing bacterial load in the lungs as a standard-of-care combination therapy involving four different drugs.
The study also assessed the new compounds' metabolic stability and cytotoxicity. Results indicated that the new rifamycins were generally less metabolically labile than rifabutin and demonstrated favorable cytotoxicity profiles in cell culture assays.
LimitationsThe authors acknowledged that the study had some limitations. The compounds' pharmacokinetics and pharmacodynamics were primarily evaluated in murine models of acute lung infection. While these results are promising, further research is needed to confirm their applicability to humans. Additionally, the study did not assess activity against M. Abscessus in biofilm-like structures or chronic infection models, which are relevant to persistent human disease and represent areas for future investigation.
ConclusionsIn summary, the research successfully identified new rifamycin analogs, specifically the preclinical development candidates UMN-120 and UMN-121, with enhanced activity against M. Abscessus and reduced potential for drug-drug interactions. These findings offer a promising avenue for developing improved treatments for M. Abscessus lung infections and potentially safer, more effective regimens for Tuberculosis, supporting their advancement towards clinical evaluation and bringing hope to patients with comorbidities such as HIV and cystic fibrosis.
Journal reference:
MRX-5 To Treat Mycobacterium Abscessus Infections
To read the full story, subscribe or sign in.Infection
May 9, 2024
New treatment options for treating Mycobaterium abscessus infections are needed. Previous findings had identified the leucyl-tRNA synthetase inhibitor MRX-6038 to have significant activity against M. Abscessus. The aim of this new study was to focus on the activity of MRX-5, the oral prodrug of MRX-6038, both in vivo and in vitro.
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