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Hit evaluation of an α-helical peptide: Ala-scan, truncation and sidechain-to-sidechain macrocyclization of an RNA polymerase Inhibitor.RNA polymerase (RNAP) remains a relatively underexplored target with only rifampicin and fidaxomicin in clinical use. Hence, the concurrent rise in bacterial resistance rate urges the search for novel RNAP inhibitors with novel mode of action. In this work, we investigated the impact of several systematic modifications including sidechain-to-sidechain macrocylization in α-helical content and biological activity of a previously identified inhibitory sigma factor fragment. Ala-scan results, peptide truncation from both the N- and C- terminus, and modifications inspired by other RNAP inhibitors revealed novel structure activity relationships but did not yield a superior sequence. Additionally, four insertion points for non-natural amino acids bearing side chains required for macrocylization were explored. Linear precursors showed improved stabilization of α-helical content compared to the original sequence as demonstrated by CD spectroscopy. However, this increase in α-helicity did not translate into improved biological activity. Instead, complete abolishment of RNAP inhibitory activity occurred. We hypothesize three possible reasons for such discrepancy and offer basis for further optimization efforts for this peptidic RNAP inhibitor.