This study evaluates the antimycobacterial potential of novel "mutual" bioactive amides, combining pyridine-4-carbohydrazide (isoniazid, INH) with various antimicrobial agents (sulphonamides, 4-aminosalicylic acid, thiosemicarbazide, diphenyl (thio)ethers) via oxocarboxylic acids. The aim was to enhance activity against both drug-susceptible and multidrug-resistant (MDR) Mycobacterium tuberculosis and non-tuberculous strains, while overcoming drug resistance through dual-action mechanisms. Many derivatives exhibited potent antimycobacterial activity, with minimum inhibitory concentrations (MICs) as low as ≤0.25 μM, outperforming INH, especially diphenyl (thio)ethers and biphenyl analogues. Additionally, the compounds were effective against M. kansasii (MICs ≤1 μM) and inhibited MDR strains at higher concentrations (≥8 μM). The cytotoxicity assay indicated a favourable safety profile, with no significant haemolysis at 125 μM, and some compounds were even protective. Selectivity for mycobacteria was confirmed by low inhibition of Gram-positive bacteria and inactivity against Gram-negative bacteria or fungi, highlighting the potential for further development as antimycobacterial agents.

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