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The large conformational changes observed by Molecular Dynamics simulation studies on the product release in the LID and shikimic acid binding (SB) domains of the shikimate kinase (SK) enzyme have been exploited in the development of reversible competitive inhibitors against SK from Mycobacterium tuberculosis and Helicobacter pylori. This enzyme is a recognized target for antibiotic drug discovery. The reported C5-substituted shikimic acid analogues interact with the dynamic apolar pocket that surrounds the C4 and C5 hydroxyl groups of the natural substrate, cause the opening of the LID and SB domains, and capture the essential arginine far from the ATP binding site as required for catalysis. The 3-nitrobenzyl 3e and 5-benzothiophenyl derivatives 3i proved to be the most potent inhibitors. An ester prodrug of 3i was the most efficient derivative in achieving good in vitro activity against H. pylori, having a MIC value of 4 μg/mL Financial support from the Spanish Ministry of Economy and Competiveness (SAF2013-42899-R), Xunta de Galicia (GRC2013-041) and the European Regional Development Fund (ERDF) is gratefully acknowledged. V.P. and M.M. thank the Spanish Ministry of Economy and Competiveness and the Spanish Ministry of Education for their respective FPI and FPU fellowships. E.L. thanks the Xunta de Galicia for his postdoctoral fellowship. J.C.V.-U. and A.B. thank the Miguel Servet Programme ISCIII-FEDER (CP13/00226) and the ISCIII General Subdirection of Assesment and Promotion of the Research (PI14/00059) for financial support SI