Targeting bacterial transcription factors for infection control: opportunities and challenges

Abstract

ABSTRACT The rising threat of antibiotic resistance in pathogenic bacteria emphasizes the need for new therapeutic strategies. This review focuses on bacterial transcription factors (TFs), which play crucial roles in bacterial pathogenesis. We discuss the regulatory roles of these factors through examples, and we outline potential therapeutic strategies targeting bacterial TFs. Specifically, we discuss the use of small molecules to interfere with TF function and the development of transcription factor decoys, oligonucleotides that compete with promoters for TF binding. We also cover peptides that target the interaction between the bacterial TF and other factors, such as RNA polymerase, and the targeting of sigma factors. These strategies, while promising, come with challenges, from identifying targets to designing interventions, managing side effects, and accounting for changing bacterial resistance patterns. We also delve into how Artificial Intelligence contributes to these efforts and how it may be exploited in the future, and we touch on the roles of multidisciplinary collaboration and policy to advance this research domain. Abbreviations: AI, artificial intelligence; CNN, convolutional neural networks; DTI: drug-target interaction; HTH, helix-turn-helix; IHF, integration host factor; LTTRs, LysR-type transcriptional regulators; MarR, multiple antibiotic resistance regulator; MRSA, methicillin resistant Staphylococcus aureus; MSA: multiple sequence alignment; NAP, nucleoid-associated protein; PROTACs, proteolysis targeting chimeras; RNAP, RNA polymerase; TF, transcription factor; TFD, transcription factor decoying; TFTRs, TetR-family transcriptional regulators; wHTH, winged helix-turn-helix.