Carbapenems, the last line of defense against serious bacterial infections, are increasingly ineffective against pathogens that produce metallo-β-lactamases (MBLs) such as VIM-2. These enzymes enable bacteria to resist carbapenem treatment, and there are currently no approved inhibitors targeting these enzymes in clinical settings. Although, recent research suggests that exploiting the growth limitations of VIM-2-expressing bacteria in zinc-deprived environments could offer a potential therapeutic strategy.1
A new study has shown that VIM-2-expressing bacteria exhibit impaired growth in environments with low zinc, such as human serum and murine infection models. The researchers used a variety of molecular tools, including transcriptomic, genomic, and chemical probes, to identify critical pathways involved in VIM-2 expression under zinc scarcity. One key discovery is that disrupting the bacterial envelope stress response pathways reduces the growth of VIM-2-expressing bacteria both in laboratory conditions and animal models.1
The research also revealed that VIM-2 expression compromises the integrity of the bacterial outer membrane, making these bacteria more susceptible to certain antibiotics, particularly azithromycin. Azithromycin is typically used to treat respiratory and gastrointestinal infections, but it is not commonly effective against Gram-negative bacteria like those that express VIM-2. The study demonstrated, however, that the envelope stress caused by zinc limitation makes these bacteria more vulnerable to azithromycin, suggesting a potential new therapeutic use for the antibiotic.1
In a systemic murine infection model, the team showed that azithromycin could be used effectively to treat infections caused by VIM-2-expressing bacteria. This discovery opens up new avenues for the treatment of multidrug-resistant infections and emphasizes the importance of exploiting the fitness trade-offs associated with antibiotic resistance.1
To further explore the implications of these findings, we spoke with researcher Megan M Tu in an exclusive email interview. Tu highlighted the critical role of zinc in bacterial growth, explaining, “Host zinc-sequestering proteins effectively deprive VIM-2-expressing bacteria of zinc, leading to misfolded proteins and envelope stress. This zinc limitation results in slower growth and heightened susceptibility to antibiotics, such as azithromycin,” as the stress caused by zinc deficiency compromises the bacterial envelope, allowing antibiotics to penetrate more effectively. Tu added, “This increased susceptibility arises because the stress caused by zinc limitation compromises the bacterial envelope, allowing antibiotics with typically low activity against Gram-negative bacteria to penetrate more effectively.”
A key finding from the study was the identification of envelope stress response pathways. By disrupting these pathways, the researchers were able to reduce the growth of VIM-2-expressing bacteria both in vitro and in vivo. This insight offers valuable information for developing new therapeutic strategies to combat these antibiotic-resistant pathogens.
Tu emphasized the importance of azithromycin in treating VIM-2-expressing pathogens, noting, “Existing antibiotics like azithromycin offer a promising alternative for treating VIM-2 and other metallo-β-lactamase (MBL)-producing pathogens, either alone or in combination with other antibiotics, such as carbapenems.” She added, “While our focus was on VIM-2, previous studies have demonstrated azithromycin's potential against other MBL-producing pathogens, suggesting its broader applicability.”2 This finding underscores the potential of azithromycin as an essential tool in treating infections caused by MBL-producing bacteria, especially considering the lack of clinically approved MBL inhibitors.
What You Need To Know
VIM-2-expressing bacteria show impaired growth and increased susceptibility to antibiotics like azithromycin in zinc-deprived environments, highlighting a potential therapeutic strategy.
Disrupting the bacterial envelope stress response pathways reduces the growth of VIM-2-expressing bacteria, offering a novel approach to treating multidrug-resistant infections.
Azithromycin demonstrates promise against VIM-2-expressing pathogens, suggesting its potential use, especially in combination therapies, for combating multidrug-resistant infections.
The therapeutic potential of azithromycin was further validated in a murine infection model, where it showed promise in treating VIM-2-expressing pathogens. Tu said “This supports the therapeutic potential of azithromycin, either alone or in combination with a carbapenem antibiotic, for the treatment of VIM-2-expressing bacteria.” This approach offers a new avenue for treating multidrug-resistant infections, with azithromycin emerging as a promising solution to counter the rise of MBL-producing pathogens.
Despite the promising results, Tu acknowledged the challenges of translating these findings into clinical therapies. She said, “Zinc levels vary across individuals, tissues, and infection sites, which makes it challenging to generalize therapeutic approaches.” She emphasized, “Implementing azithromycin therapy against VIM-expressing bacteria would need to be clinically tested” to assess its efficacy across diverse patient populations and infection conditions.
While the discovery of therapeutic strategies targeting zinc limitation is promising, Tu emphasized the next steps in this research, “The goal is to exploit the fitness trade-offs of resistance, potentially accelerating the discovery of additional treatments for infections caused by multidrug-resistant bacteria.” By focusing on the vulnerabilities of bacteria that express metallo-β-lactamases, researchers may pave the way for new strategies that could improve patient outcomes in the fight against antibiotic resistance.
In conclusion, this study outlines the mechanisms of VIM-2 resistance and suggests a therapeutic approach targeting zinc limitation and stress response pathways. Tu’s insight into how “zinc limitation disrupts the bacterial envelope, leading to greater susceptibility to antibiotics like azithromycin” offers a potential strategy to address antibiotic resistance. As research advances, this approach could help combat carbapenem-resistant pathogens.
References
1. Tu MM, Carfrae LA, Rachwalski K, et al. Exploiting the fitness cost of metallo-β-lactamase expression can overcome antibiotic resistance in bacterial pathogens. Nat Microbiol. 2025;10(1):53-65. doi:10.1038/s41564-024-01883-8
2. Herencias, C., Álvaro-Llorente, L., Ramiro-Martínez, P. et al. β-lactamase expression induces collateral sensitivity in Escherichia coli. Nat Commun 15, 4731 (2024). https://doi.org/10.1038/s41467-024-49122-2
