TY - JOUR
T1 - Repurposing of apoptotic inducer drugs against Mycobacterium tuberculosis
AU - Nyambo, Kudakwashe
AU - Soko, Vivette
AU - Tapfuma, Kudzanai Ian
AU - Motaung, Bongani
AU - Adu-Amankwaah, Francis
AU - Julius, Lauren
AU - Klein, Ashwil
AU - Keyster, Marshall
AU - Baatjies, Lucinda
AU - Smith, Liezel
AU - Govender, Krishna Kuben
AU - Ngxande, Mkhuseli
AU - Loxton, Andre G.
AU - Mavumengwana, Vuyo
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - Computational approaches complement traditional in-vitro or in-vivo assays, significantly accelerating the drug discovery process by increasing the probability of identifying promising lead compounds. In this study, the apoptotic compounds were assessed for antimycobacterial activity and immunomodulatory potential in infected THP-1 macrophage cells. The antimycobacterial activity of the apoptotic compounds was evaluated using the minimum inhibitory concentration (MIC) assay. The immunomodulatory potential of the apoptotic compounds was determined on mycobacterial-infected THP-1 and non-infected THP-1 macrophage cells. The potential binding dynamics of the compounds against InhA were predicted using molecular docking, molecular dynamics, and MM-GBSA binding free energies. The in-vitro MIC assay showed that cepharanthine (CEP) had the highest antimycobacterial activity against Mycobacterium smegmatis mc2155 and Mycobacterium tuberculosis H37Rv, with MICs of 3.1 and 1.5 µg/mL, respectively, followed by CP-31398 dihydrochloride hydrate (DIH) (MICs = 6.2 and 3.1 µg/mL, respectively), marinopyrrole A (MAR) (MICs = 25 and 12.5 µg/mL, respectively), and nutlin-3a (NUT) (MICs = 50 and 25 µg/mL, respectively). MICs for the rest of the drugs were > 200 µg/mL against both M. smegmatis mc2155 and M. tuberculosis H37Rv. Furthermore, the growth of M. smegmatis mc2155 in infected THP-1 macrophage cells treated with DIH, CEP, carboxyatractyloside potassium salt (CAR), and NUT was inhibited by the mentioned drugs. Cytokine profiling showed that DIH optimally regulated the secretion of IL-1β and TNF-α which potentially enhanced the clearance of the intracellular pathogen. Molecular dynamics simulations showed that NUT, MAR, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), and BV02 strongly bind to InhA. However, 17-AAG and BV02 did not show significant activity in-vitro. This study highlights the importance of probing already existing chemical scaffolds as a starting point for discovery of therapeutic agents against M. tuberculosis H37Rv using both pathogen and host directed approaches. The integration of molecular dynamics simulations provides valuable insights into potential scaffold modifications to enhance the affinity.
AB - Computational approaches complement traditional in-vitro or in-vivo assays, significantly accelerating the drug discovery process by increasing the probability of identifying promising lead compounds. In this study, the apoptotic compounds were assessed for antimycobacterial activity and immunomodulatory potential in infected THP-1 macrophage cells. The antimycobacterial activity of the apoptotic compounds was evaluated using the minimum inhibitory concentration (MIC) assay. The immunomodulatory potential of the apoptotic compounds was determined on mycobacterial-infected THP-1 and non-infected THP-1 macrophage cells. The potential binding dynamics of the compounds against InhA were predicted using molecular docking, molecular dynamics, and MM-GBSA binding free energies. The in-vitro MIC assay showed that cepharanthine (CEP) had the highest antimycobacterial activity against Mycobacterium smegmatis mc2155 and Mycobacterium tuberculosis H37Rv, with MICs of 3.1 and 1.5 µg/mL, respectively, followed by CP-31398 dihydrochloride hydrate (DIH) (MICs = 6.2 and 3.1 µg/mL, respectively), marinopyrrole A (MAR) (MICs = 25 and 12.5 µg/mL, respectively), and nutlin-3a (NUT) (MICs = 50 and 25 µg/mL, respectively). MICs for the rest of the drugs were > 200 µg/mL against both M. smegmatis mc2155 and M. tuberculosis H37Rv. Furthermore, the growth of M. smegmatis mc2155 in infected THP-1 macrophage cells treated with DIH, CEP, carboxyatractyloside potassium salt (CAR), and NUT was inhibited by the mentioned drugs. Cytokine profiling showed that DIH optimally regulated the secretion of IL-1β and TNF-α which potentially enhanced the clearance of the intracellular pathogen. Molecular dynamics simulations showed that NUT, MAR, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), and BV02 strongly bind to InhA. However, 17-AAG and BV02 did not show significant activity in-vitro. This study highlights the importance of probing already existing chemical scaffolds as a starting point for discovery of therapeutic agents against M. tuberculosis H37Rv using both pathogen and host directed approaches. The integration of molecular dynamics simulations provides valuable insights into potential scaffold modifications to enhance the affinity.
KW - Cytokine profiling
KW - Drug repurposing
KW - Host-directed therapy
KW - Molecular dynamics simulation
KW - Tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=85219641470&partnerID=8YFLogxK
U2 - 10.1038/s41598-025-91096-8
DO - 10.1038/s41598-025-91096-8
M3 - Article
AN - SCOPUS:85219641470
SN - 2045-2322
VL - 15
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 7109
ER -