Macrolide Plus Nucleoside Combo Curbs SARS-CoV-2 and Shields Monkey Lungs

A combination of the macrolide antibiotic Carrimycin and the nucleoside analogue Azvudine suppressed SARS-CoV-2 replication more effectively than either drug alone in rhesus macaques, while also easing lung injury and correcting immune dysregulation, according to a study published in the Journal of Translational Medicine. The work, led by researchers at the Chinese Academy of Medical Sciences and Peking Union Medical College, addresses a persistent gap in COVID-19 therapeutics: most current antivirals target viral replication alone and offer little protection against the immunoinflammatory damage that drives severe disease.

The rationale for the combination rests on the complementary profiles of the two drugs. Azvudine, known chemically as FNC, is a nucleoside reverse transcriptase inhibitor approved in China for HIV treatment and later authorized for COVID-19. As an analogue, it is incorporated by viral polymerases and terminates RNA synthesis, acting directly on the SARS-CoV-2 RNA-dependent RNA polymerase. Carrimycin, by contrast, is a macrolide derived from the engineered antibiotic compound 4″-O-isovalerylspiramycin. Macrolides are best known as antibacterials, but several members of the class display immunomodulatory and anti-inflammatory properties, and Carrimycin has previously shown antiviral activity against coronaviruses. Pairing a direct-acting polymerase inhibitor with an agent that modulates host responses is an appealing strategy precisely because evolving SARS-CoV-2 variants have begun to erode the effectiveness of replication-targeted monotherapy.

To test the concept, the team turned to rhesus macaques, which remain among the most faithful animal models of human COVID-19 because they develop viral pneumonia, radiographic abnormalities, and immune responses that closely mirror clinical disease. Animals were inoculated intratracheally with SARS-CoV-2 and then treated orally for seven days with Carrimycin at 9 milligrams per kilogram, Azvudine at 0.07 milligrams per kilogram, or the two drugs together. The researchers then tracked viral loads, lung pathology, immune responses, and gut microbiota across the treatment groups, conducting the work in an animal biosafety level 3 facility under protocols approved by the institutional animal care committee.

The antiviral results were clear-cut. Both monotherapies significantly inhibited SARS-CoV-2 replication, but the combination produced additive effects, driving viral loads down further in both throat swabs and lung tissue. That pattern matters because viral burden in the lower respiratory tract correlates with disease severity and onward transmission risk. Notably, the authors reported no significant side effects in the treated animals, an important consideration for a combination intended for clinical use, since drug-drug interactions and cumulative toxicity often limit real-world combination regimens.

Lung protection was assessed by chest imaging and histopathology, and here the combination again outperformed either drug alone. Monotherapy reduced ground-glass opacities, the hazy areas on chest scans that reflect fluid and inflammatory infiltration of lung tissue, and mitigated focal interstitial pneumonia, the inflammation of the tissue between air sacs that characterizes severe COVID-19. The combination treatment demonstrated superior efficacy on both measures, suggesting that blunting viral replication while simultaneously damping host inflammation preserves lung architecture more effectively than either intervention alone.

To understand how the combination reshaped the lung environment, the researchers performed transcriptomic profiling and immunofluorescence staining of lung tissue. Gene expression analysis revealed enhanced immunomodulation under combination therapy, including suppression of neutrophil degranulation, a process in which activated neutrophils release enzymes and antimicrobial proteins that, when excessive, damage surrounding tissue and contribute to acute lung injury. The combination also increased populations of CD19-positive B cells and CD3-positive T cells, the cornerstones of adaptive humoral and cellular immunity, while decreasing CD68-positive macrophages, whose accumulation in the lung is associated with sustained inflammation.

At the molecular level, combination therapy downregulated pro-inflammatory and apoptotic markers, pointing to reduced inflammatory signaling and less programmed cell death in infected lung tissue. Taken together, these findings suggest the combination does more than lower viral numbers; it shifts the lung immune landscape away from the maladaptive innate hyperinflammation seen in severe COVID-19 and toward a more effective adaptive response. That distinction is clinically significant, because mortality in severe COVID-19 is driven as much by immunopathology as by the virus itself, and therapies that address both axes have been sought since the beginning of the pandemic.

The study also uncovered a difference between the two drugs that monotherapy comparisons alone would have missed. Carrimycin, but not Azvudine, increased gut bacteria that produce short-chain fatty acids, metabolites with well-documented anti-inflammatory and immune-regulatory effects, and decreased harmful pathogens previously associated with COVID-19 progression. The gut-lung axis, the bidirectional communication between intestinal microbes and respiratory immunity, has emerged as a contributor to COVID-19 outcomes, and dysbiosis has been linked to worse disease. A drug that simultaneously acts on the lung and restores a favorable microbiome composition could therefore offer benefits beyond direct antiviral activity, potentially supporting recovery and reducing secondary complications.

The authors conclude that the Carrimycin-Azvudine combination showed superior efficacy in suppressing viral replication, alleviating lung injury, and correcting immune and inflammatory dysregulation, with Carrimycin providing additional gut microbiota benefits. They position the pairing as a promising therapeutic strategy against COVID-19 and its complications, particularly in a landscape where ongoing viral mutation, emerging resistance mutations, inadequate immunomodulation, and suboptimal organ protection limit existing antiviral options. The work was supported by the National Natural Science Foundation of China, the National Key Research and Development Program of China, and the CAMS Innovation Fund for Medical Sciences.

As with any preclinical animal study, the path from macaques to patients requires clinical validation, including pharmacokinetic confirmation of the doses used, human safety data for the combination, and efficacy trials in infected populations. Nevertheless, the study offers a mechanistically grounded template for next-generation COVID-19 therapy: a direct-acting antiviral paired with an immunomodulatory and microbiome-friendly partner, evaluated with the full toolkit of modern virology, imaging, transcriptomics, and metagenomics. If the additive antiviral and lung-protective effects observed here translate to humans, the combination could address precisely the shortcomings, resistance, inflammation, and organ damage, that have constrained single-drug approaches throughout the pandemic.

Subject of Research: Combination antiviral therapy with Carrimycin and Azvudine against SARS-CoV-2 infection in rhesus macaques

Article Title: Better antiviral and lung-protective effects of Carrimycin in combination with Azvudine in rhesus macaques infected with SARS-CoV-2

Article References: Li, H., Liu, Y., Xue, J., Li, J., Xu, J., Dong, B., Wang, T., Peng, X., Che, Y., Jiang, J., & Peng, Z. (2026). Better antiviral and lung-protective effects of Carrimycin in combination with Azvudine in rhesus macaques infected with SARS-CoV-2. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08933-1

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08933-1

Keywords: SARS-CoV-2, Carrimycin, Azvudine, combination therapy, rhesus macaques, lung injury, immunoinflammatory regulation, gut microbiota, antivirals, macrolides, COVID-19, translational medicine