Auxin (Indole-3-acetic acid) modulation of quorum sensing enhances phage susceptibility in Klebsiella pneumoniae

Klebsiella pneumoniae is a multidrug-resistant (MDR) bacterium that has emerged as a major global public health threat. The decreasing effectiveness of conventional antibiotics has renewed interest in bacteriophage therapy as a promising alternative antibacterial strategy. However, the rapid emergence of phage resistance remains a critical limitation. This study aimed to investigate whether indole-3-acetic acid (IAA) can modulate bacterial quorum sensing (QS) and enhance phage therapy by modulating the QS regulator SdiA. Experiments were performed using the lytic bacteriophage VAC7 and a clinical K. pneumoniae ST16-OXA48 strain. The minimum inhibitory concentration (MIC) of IAA was determined, and sub-inhibitory concentrations were used to assess QS gene expression by RT-qPCR, phage infection dynamics, and bacterial proteomic responses. RT-qPCR analysis demonstrated that IAA significantly reduced the expression of the QS regulator gene sdiA while increasing luxS expression. Phage infection assays showed enhanced bactericidal activity of VAC7 against the ST16-OXA48 clinical isolate in the presence of IAA. Proteomic analysis revealed a reduced abundance of several bacterial phage defense proteins in the presence of IAA, including GmrSD restriction endonuclease, bacteriophage control infection (BCI), mRNA interferase PemK, and abortive infection protein. Proteins associated with phage receptors, such as LamB, OmpK36, OmpC, and FhuA, were detected under all conditions but reduced when the phage is present. The detection of multiple phage structural, functional and anti-phage defense system proteins was consistent with active phage replication. IAA, a plant-derived auxin, modulates bacterial QS and SdiA, and reduces phage resistance mechanisms in K. pneumoniae. These findings highlight the potential of IAA, and possibly other auxins, as adjuvants in phage therapy and as versatile components of combination antimicrobial strategies.