PREreview of In vitroandin vivosynergy of Vancomycin and β-lactams against drug-resistantMycobacterium tuberculosisand Non-tuberculous mycobacteria

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.