In vitro and in vivo synergy of Vancomycin and β-lactams against drug-resistant Mycobacterium tuberculosis and Non-tuberculous mycobacteria
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Abstract
The unabated increase in antimicrobial resistance has underlined the importance of identifying novel drug combinations which eliminate infections more potently and likely reduce the emergence of resistance. In this context, we have identified Vancomycin and many β-lactams as being potently active against drug-resistant Mycobacterium tuberculosis and non-tuberculous mycobacteria including M. abscessus, emerging as pathogens of concern owing to their inherent drug resistance profile. In this study, we have identified combinations of Vancomycin, a glycopeptide and β-lactams, especially Ceftriaxone, Ceftazidime and Meropenem, in the presence or absence of Sulbactam, a β- lactamase inhibitor, as possessing potent antimicrobial activity against several drug-resistant mycobacterial strains. The combination of Vancomycin and β-lactams exhibited potent bactericidal activity and reduced the bacterial load better than either drug alone. The molecular basis of synergy was mediated by increase in permeability of mycobacterial cell as demonstrated by ethidium bromide assay. In the murine model of mycobacterial infection, synergistic combination of Vancomycin and β-lactams outperformed clinically utilized drugs including Isoniazid, Rifampicin and Ethambutol against M. tuberculosis and Amikacin, Clarithromycin against M. abscessus . The combinations caused a significant reduction in bacterial load in various organs in M. tuberculosis and M. abscessus infected mice. Thus, the synergistic combination of Vancomycin and β-lactams could potentially be utilized for treatment of recalcitrant mycobacterial infection especially those caused due to drug-resistant pathogens.
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This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/15219839.
Summary:
This preprint investigated the synergistic potential of Vancomycin (VAN), a glycopeptide antibiotic, and various β-lactams (BLs), including Ceftriaxone (CRO), Ceftazidime (CAZ), and Meropenem (MEM), in combating drug-resistant Mycobacterium tuberculosis (Mtb) and non-tuberculous mycobacteria (NTMs) such as M. abscessus. In vitro and in vivo data demonstrated that combinations of Vancomycin + β-lactams and their augmentation with Sulbactam (SUL) significantly outperformed current frontline drugs, including Isoniazid and Rifampicin, in reducing bacterial loads.
Key contributions of the study:
Identification of VAN+BL synergy in both Mtb and NTMs
Novel in vivo validation, expanding on …
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/15219839.
Summary:
This preprint investigated the synergistic potential of Vancomycin (VAN), a glycopeptide antibiotic, and various β-lactams (BLs), including Ceftriaxone (CRO), Ceftazidime (CAZ), and Meropenem (MEM), in combating drug-resistant Mycobacterium tuberculosis (Mtb) and non-tuberculous mycobacteria (NTMs) such as M. abscessus. In vitro and in vivo data demonstrated that combinations of Vancomycin + β-lactams and their augmentation with Sulbactam (SUL) significantly outperformed current frontline drugs, including Isoniazid and Rifampicin, in reducing bacterial loads.
Key contributions of the study:
Identification of VAN+BL synergy in both Mtb and NTMs
Novel in vivo validation, expanding on previous in vitro studies
Mechanistic insights through cell wall permeability and electron microscopy
Potential to repurpose known drugs for drug-resistant TB and NTMs
Review:
This study offered a compelling strategy to overcome drug resistance using known antibiotics. If validated further, this approach could shape future treatment regimens, particularly for resistant non-tuberculous mycobacteria, which currently lack robust therapies. The technical innovations mentioned in the study were not based on novel compounds, but the approach is innovative in its repurposing and combination of existing antibiotics. The robust in vivo validation added originality to the literature. Prior literature was mentioned and acknowledged appropriately in the study, and there were found to be no apparent commercial biases. Also, the study used concurrent findings to build upon these research studies. Presentation of the preprint was mostly strong as the manuscript was generally well-organized. However, minor issues such as grammatical inconsistencies and occasionally awkward phrasing detract from readability. Figures are clear and well-labeled, but a few legends could be more concise and shortened as they are a bit unreadable and long. The quality of data and the analytical techniques used in the study were very strong, as minimum inhibitory concentrations, checkerboard assays, time-kill kinetics, EtBr uptake, fluorescence microscopy, and scanning electron microscopy were appropriately used. Data was accurately presented in tables and graphs clearly, and the analytical methods were standard and robust. The conclusions were found to be well-supported by the data as the authors appropriately noted that the in vivo impact of Sulbactam was limited, which added credibility to their discussion. It would be better to add significant indicators (e.g., , **, ns) directly onto bar graphs or line charts where comparisons are made, as well as polish the language of the study since while it is mostly readable, the manuscript would benefit from a round of professional copy editing to improve fluency. It would be good to ensure that there is consistent terminology within the study. Additionally, reducing repetitive explanations of methods already detailed in the Materials and Methods section would be best.
Competing interests
The author declares that they have no competing interests.
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