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. 2020 Oct 9;11:563944. doi: 10.3389/fmicb.2020.563944

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Copyright © 2020 Das and Bhadra.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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A schematic representation showing the (p)ppGpp mediated antimicrobial resistance (AMR) in bacteria. Except AMR cassette acquisition at the integron integrase locus all other processes that are directly or indirectly associated with antibiotic resistance due to increased level of (p)ppGpp are non-inheritable. (p)ppGpp induces antibiotic resistance in bacteria via distinct mechanisms (see details in text), which are as follows. (i) (p)ppGpp increases the efficiency of horizontal gene transfer (HGT) and AMR cassette acquisition by derepressing the integron integrase 1 (intI1) gene promoter (P_intI1). Elevated level of (p)ppGpp induces autoproteolytic activity of SOS response master regulator LexA, and thus increases expression of the intI1 gene. In addition, SOS induction also derepressed the expression of error-prone DNA polymerase IV (Pol IV) and upturns accumulation of spontaneous point mutations via DNA replication, which in turn escalates development of resistant variants. (ii) (p)ppGpp upregulates the expression of the aminoglycoside adenylyl transferase gene (aadA), penicillin binding protein coding gene (pbp), and different components of the efflux pumps. (iii) (p)ppGpp helps DksA to compete with microcin J25 (MccJ25) peptide antibiotic for binding with RNA polymerase (RNAP) and confers resistance against this peptide antibiotic. (iv) (p)ppGpp represses the expression of aconitase B (AcnB) and suppresses tricarboxylic acid (TCA) cycle and increases non-inheritable resistance to antibiotics. (v) (p)ppGpp represses the expression of Fe(III) ABC transporter substrate-binding protein (FbpA) and activates superoxide dismutase (SOD) activity. Both the modulations reduce the level of reactive oxygen species (ROS) leading to increase in resistance against tetracycline and other antibiotics. Solid arrows indicate activating interactions and T-arrows indicate inhibiting interactions. Bent arrows at the integron locus indicate promoter for AMR cassette (Pc) and P_intI1. MitC^R, Mitomycin C resistance; Nitf^R, Nitrofurantoin resistance.