Production of beta-lactamases, the enzymes that degrade beta-lactam antibiotics, is the most widespread and threatening mechanism of antibiotic resistance. In the past, extensive research has focused on the structure, function, and ecology of beta-lactamases while limited efforts were placed on the regulatory mechanisms of beta-lactamases. Recently, increasing evidence demonstrate a direct link between beta-lactamase induction and cell wall metabolism in Gram-negative bacteria. Specifically, expression of beta-lactamase could be induced by the liberated murein fragments, such as muropeptides. This article summarizes current knowledge on cell wall metabolism, beta-lactam antibiotics, and beta-lactamases. In particular, we comprehensively reviewed recent studies on the beta-lactamase induction by muropeptides via two major molecular mechanisms (the AmpG–AmpR–AmpC pathway and BlrAB-like two-component regulatory system) in Gram-negative bacteria. The signaling pathways for beta-lactamase induction offer a broad array of promising targets for the discovery of new antibacterial drugs used for combination therapies. Therefore, to develop effective mitigation strategies against the widespread beta-lactam resistance, examination of the molecular basis of beta-lactamase induction by cell wall fragment is highly warranted.

Background: Campylobacter jejuni is a leading pathogen causing gastroenteritis in humans. Invasive C. jejuni strains crossing the gut-blood barrier can cause bacteremia. Despite its microaerophilicity (preferring <5% O ₂ atmosphere), hyper-aerotolerant (HAT) C. jejuni has recently been isolated from intestines in poultry and humans. Elevated aerotolerance may enhance C. jejuni survival in the ecosystem, thereby promoting its transmission. However, invasive HAT isolates of C. jejuni have not been reported in bacteremia in humans. Case Summary: A C. jejuni strain (CNH-HAT-1) was isolated from a 7% CO ₂ (~16% O ₂ ) atmosphere subculture of an aerobic blood culture from a 5-year-old boy with B-cell acute lymphoblastic leukemia presenting with bloody stool, fever, and neutropenia. The organism identification was determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and 16S-rRNA sequencing. HAT phenotype of this isolate was confirmed by aerotolerance testing. Belonging to the ST-21 clonal complex, CNH-HAT-1 is phylogenetically close to recently reported invasive C. jejuni sheep abortion strains and some bacteremia-associated strains. CNH-HAT-1 possesses a CJIE-1 prophage element, a functional enterobactin receptor CfrB, and G250A mutation in the major outer-membrane protein PorA, which likely contributes to C. jejuni invasiveness. CNH-HAT-1 is resistant to penicillins/cephalosporins but susceptible to aminoglycosides, fluoroquinolones, and macrolides. The patient improved with intravenous gentamicin, followed by enteral therapy with azithromycin. Conclusion: We identified a novel invasive bloodstream C. jejuni strain proven in vitro to be HAT, shedding light on key genomic features linking with its pathogenesis. Given its enhanced survival of HAT C. jejuni in ecosystem, a clinical microbiology lab should be vigilant with detecting them from blood cultures.

Campylobacter jejuni is the leading bacterial cause of human enteritis in developed countries. Chicken is the major animal reservoir of C. jejuni and a powerful infection model for human campylobacteriosis. No commercial vaccine against C. jejuni is available to date. The high affinity iron acquisition mediated through enterobactin (Ent), a small siderophore, plays a critical role in the colonization of C. jejuni in the intestine. Recently, an innovative Ent conjugate vaccine has been demonstrated to induce high-level of Ent-specific antibodies in rabbits; the Ent-specific antibodies displayed potent binding ability to Ent and inhibited Ent-dependent growth of C. jejuni. In this study, using specific-pathogen-free (SPF) chickens, we performed three trials to evaluate the immunogenicity of the Ent conjugate vaccine and its efficacy to control C. jejuni colonization in the intestine. The purified Ent was conjugated to the carrier keyhole limpet hemocyanin (KLH). Intramuscular immunization of chickens with the Ent–KLH conjugate for up to three times did not affect the body weight gain, the development of major immune organs and the gut microbiota. In the first two trials, immunizations of chickens with different regimens (two or three times of vaccination) consistently induced strong Ent-specific immune response when compared to control group. Consistent with the high-level of systemic anti-Ent IgG, C. jejuni colonization was significantly reduced by 3–4 log₁₀ units in the cecum in two independent vaccination trials. The third trial demonstrated that single Ent–KLH vaccination is sufficient to elicit high level of systemic Ent-specific antibodies, which could persist for up to eight weeks in chickens. Taken together, the Ent–KLH conjugate vaccine could induce high-level of Ent-specific antibodies in chickens and confer host protection against C. jejuni colonization, which provides a novel strategy for Campylobacter control in poultry and humans.