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The growing antimicrobial resistance to last-line antimicrobials among Gram-positive pathogens remains a major healthcare emergency worldwide. Therefore, the search for new small molecules targeting multidrug-resistant pathogens remains of great importance. In this paper, we report the synthesis and in vitro antimicrobial activity characterisation of novel thiazole derivatives using representative Gram-negative and Gram-positive strains, including tedizolid/linezolid-resistant <i>S. aureus,</i> as well as emerging fungal pathogens. The 4-substituted thiazoles <b>3h</b>, and <b>3j</b> with naphthoquinone-fused thiazole derivative <b>7</b> with excellent activity against methicillin and tedizolid/linezolid-resistant <i>S. aureus</i>. Moreover, compounds <b>3h</b>, <b>3j</b> and <b>7</b> showed favourable activity against vancomycin-resistant <i>E. faecium</i>. Compounds <b>9f</b> and <b>14f</b> showed broad-spectrum antifungal activity against drug-resistant <i>Candida</i> strains, while ester <b>8f</b> showed good activity against <i>Candida auris</i> which was greater than fluconazole. Collectively, these data demonstrate that <i>N</i>-2,5-dimethylphenylthioureido acid derivatives could be further explored as novel scaffolds for the development of antimicrobial candidates targeting Gram-positive bacteria and drug-resistant pathogenic fungi.