Neisseria gonorrhoeae-derived outer membrane vesicles package β-lactamases to promote antibiotic resistance

Abstract

Neisseria gonorrhoeae causes the sexually transmitted disease gonorrhoea. The treatment of gonorrhoea is becoming increasingly challenging, as N. gonorrhoeae has developed resistance to antimicrobial agents routinely used in the clinic. Resistance to penicillin is wide-spread partly due to the acquisition of β-lactamase genes. How N. gonorrhoeae survives an initial exposure to β-lactams before acquiring resistance genes remains to be understood. Here, using a panel of clinical isolates of N. gonorrhoeae we show that the β-lactamase enzyme is packaged into outer membrane vesicles (OMVs) by strains expressing blaTEM-1B or blaTEM-106 which protects otherwise susceptible clinical isolates from the β-lactam drug amoxycillin. We characterized the phenotypes of these clinical isolates of N. gonorrhoeae and the time courses over which the cross-protection of the strains is effective. Imaging and biochemical assays suggest that OMVs promote the transfer of proteins and lipids between bacteria. Thus, N. gonorrhoeae strains secret antibiotic degrading enzymes via OMVs enabling survival of otherwise susceptible bacteria.

Adding to the family of resistance factors against last resort antibiotics: Identification and characterization of a novel carbapenemase, CIM-1

“…As shown in other studies, many β-lactamases that are secreted within OMVs can protect antibiotic susceptible bacteria in their surroundings against these antibiotics (Gonzalez et al, 2016;Kim et al, 2018). This phenomenon has not only been observed experimentally but has now been reported clinically (Bielaszewska, Daniel, Nyc, & Mellmann, 2021;Dhital et al, 2022). As CIM-1 has a high a nity for cephalosporins and carbapenems, it will be very effective in deactivating these antibiotics to provide resistance to an entire mix microbial population when excreted in OMVs.…”

Availability of iron ions impacts physicochemical properties and proteome of outer membrane vesicles released by Neisseria gonorrhoeae

“…Previously, it was demonstrated that N. gonorrhoeae releases OMVs 16 , 17 , 20 ; however, the iron impact on this process has yet to be evaluated. We studied the OMV secretion by N .…”

“…Already published data indicate that gonococcal OMVs influence human host cells by stimulating an immune response in non-phagocytic cells and by apoptosis induction of macrophages 17 , 19 . Recently, Dhital et al 20 demonstrated that OMVs of clinical gonococcal strains carry β-lactamase, enabling the survival of gonococci and promoting their antibiotic resistance.…”

Microbial extracellular vesicles contribute to antimicrobial resistance

“…It is noteworthy that current research indicates that bacterial EVs can transport β-lactamases outside the cell [ 42 – 44 ]. This occurs because when bacteria producing β-lactamases are under antibiotic stress, they can employ the Sec system to transport β-lactamases to the periplasmic space.…”