Modulation of Neisseria gonorrhoeae susceptibility to vertebrate antibacterial peptides due to a member of the resistance/nodulation/division efflux pump family

Abstract

We have previously described the antibacterial capacity of protegrin-1 (PG-1), a cysteine-rich, cationic peptide from porcine leukocytes, against Neisseria gonorrhoeae. We now report genetic and biochemical evidence that gonococcal susceptibility to the lethal action of PG-1 and other structurally unrelated antibacterial peptides, including a peptide (LL-37) that is expressed constitutively by human granulocytes and testis and inducibly by keratinocytes, is modulated by an energy-dependent eff lux system termed mtr. These results indicate that such eff lux systems may enable mucosal pathogens like gonococci to resist endogenous antimicrobial peptides that are thought to act during infection.

Transient cutaneous adenoviral gene therapy with human host defense peptide hCAP-18/LL-37 is effective for the treatment of burn wound infections

“…32,34 Finally, regarding the actual resistance problem of classic antibiotics and its rapid progress, it must be mentioned that there is only a very low tendency of developing resistance to HDP. 35,36 Possible systemic side effects after systemic or local applications of LL-37 still remain a field for further investigations.…”

The Role of the Transcription Factors MtrR and MtrA in the Fitness of the Pathogen Neisseria gonorrhoeae

“…Our use of the mouse model to study the consequence of mtrR mutation in N. gonorrhoeae is supported by physiological and immunological similarities between the lower genital tracts of women and female mice (44,80,204). Overexpression of the mtrCDE operon during infection may increase gonococcal evasion of natural immune effectors such as bile salts (63), progesterone (81), the human antimicrobial peptide LL-37 (176), and in the case of experimental murine infection, the cathelicidin-related protein (CRAMP). CRAMP, the murine homologue of LL-37, is expressed by epithelial cells and is present in the granules of polymorphonuclear leukocytes (178), and is known to be important in the immune response to bacterial infections (136).…”

“…The FarA-FarB pump pairs with the MtrE protein to form a functional transporter, which acts to expel long chain fatty acids (97). The MtrC-MtrD-MtrE efflux pump was the first gonococcal efflux pump described and has the widest range of pump substrates, which include bile salts, fatty acids, macrolide antibiotics, penicillin (64), hormones (81), and antimicrobial peptides (176). The NorM efflux pump recognizes cationic compounds including norfloxacin, ciprofloxacin, and ethidium bromide (158).…”

Antimicrobial Peptide Resistance Mechanisms of Human Bacterial Pathogens

“…N. gonorrhoeae express an energydependent efflux system MtrCDE that expels hydrophobic antimicrobial agents and increases resistance to antibiotics such as penicillin and erythromycin (Veal et al, 2002). Genetic and biochemical evidence has demonstrated that gonococcal resistance to protegrin-1 and human cathelicidin LL-37 is modulated by overexpression of the mtr genes (Shafer et al, 1998). S. enterica mutants with a defect in the sap locus sharing homology with potassiumlinked efflux systems in E. coli are more susceptible to the cationic AMP protamine (Parra-Lopez et al, 1994), while a homologous locus in H. influenzae promotes resistance to β-defensin (Mason et al, 2005).…”