SUMMARYSerum-sensitive mutants have been derived from serum-resistant smooth virulent Salmonella typhimurium and S. enteritidis strains by selection for resistance to cephalosporin or penicillin. Chemical analyses of the lipopolysaccharides of these mutants reveal that they belong to at least three different rough or semi-rough classes. Partial or total loss from the lipopolysaccharide of the sugars responsible for 0 antigenicity resulted in loss of virulence, as well as increased sensitivity to the bactericidal effect of antibody plus complement. However, such loss is not necessary for serum sensitivity because two serum-sensitive mutants possessed lipopolysaccharides indistinguishable from the smooth serum-resistant parents and were nearly as virulent.
Bacterial DnaK is an ATP-dependent molecular chaperone important for maintaining cellular proteostasis in concert with cofactor proteins. The cofactor DnaJ delivers nonnative client proteins to DnaK and activates its ATPase activity, which is required for protein folding. In the bacterial pathogen Mycobacterium tuberculosis, DnaK is assisted by two DnaJs, DnaJ1 and DnaJ2. Functional protein−protein interactions (PPIs) between DnaK and at least one DnaJ are essential for survival of mycobacteria; hence, these PPIs represent untapped antibacterial targets. Here, we synthesize peptide-based mimetics of DnaJ1 and DnaJ2 N-terminal domains as rational inhibitors of DnaK− cofactor interactions. We find that covalently stabilized DnaJ mimetics are capable of disrupting DnaK−cofactor activity in vitro and prevent mycobacterial recovery from proteotoxic stress in vivo, leading to cell death. Since chaperones and cofactors are highly conserved, we anticipate these results will inform the design of other mimetics to modulate chaperone function across cell types.
Mycobacterium tuberculosis (Mtb) is the main pathogenic agent of tuberculosis (TB), a leading cause of death due to an infectious disease worldwide (WHO, 2018). About a third of the world's population is estimated to have latent TB infection, reflecting Mtb's ability to survive in the human host as bacterial subpopulations in heterogeneous states that range from replicative to non-replicative, with differing sensitivities to antibiotics (Gold and Nathan, 2017). Mtb can reside in acidic host environments, as evidenced by the avirulence of acid-susceptible mutants in mice and the activity of the front-line TB drug pyrazinamide, which becomes active against Mtb in vitro under acidic conditions (
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