Functional 'omics' studies previously identified the M. tuberculosis surface located adhesins, heparin-binding hemagglutinin adhesin (HBHA) and curli pili (MTP) as significant potential targets for the design of tuberculosis (TB) point-of-care diagnostics, effective drugs, and vaccines. Little is known on the effect of these adhesins on the pathogen's transcriptome. The current study, via transcriptomics, elucidated whether the deletion of the single genes, hbhA and mtp, and double genes, hbhA-mtp, via specialised transduction, affected global bacterial gene expression. RNA sequencing of M. tuberculosis wild-type V9124 (WT), single and double deletion HBHA and MTP mutant strains were confirmed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) on selected genes, and a functional bacterial ATP bioluminescence assay. The 43 significantly differentially expressed genes amongst the deletion mutants were functionally categorized into central carbon metabolism (CCM), cell wall biosynthesis and cell wall transport and processes. The increased expression of genes associated with ATP synthase and cell wall processes were confirmed by RT-qPCR. In the absence of the adhesins, a decreased ATP concentration was observed suggesting either increased utilization or alterations to the proton motive force (PMF) that resulted in a potential inhibition of ATP synthesis. Therefore, deletions of the mtp and hbhA genes were associated with significant perturbations in CCM regulation/function, and transport of proteins to the cell wall, indicating the significant contribution of these adhesins in fundamental processes contributing to TB pathogenesis. Thus, this study indicates that MTP and HBHA influence gene expression in M. tuberculosis and represent important targets for TB diagnostic/therapeutic interventions and should be investigated as vaccine and adjunctive therapies.