The human male reproductive tract antimicrobial peptides of the HE2 family exhibit potent synergy with standard antibiotics

Abstract

Reproductive tract infections pose a serious threat to health and fertility. Due to the emergence of antibiotic resistant pathogens, antimicrobial proteins and peptides of the reproductive tract are extensively characterized in recent years toward developing newer strategies to treat genital tract infections. Pathogen growth inhibition using a combination of naturally occurring male reproductive tract antimicrobial peptides and commonly used antibiotics has not been reported. Checker board analyses were carried out to determine the nature of interaction (synergistic, additive and antagonistic) between HE2alpha and HE2beta2 peptides and the commonly used antibiotics. Using Escherichia coli as the target organism, the minimal inhibitory concentration and fractional inhibitory concentration indices were determined. We demonstrate for the first time that the human male reproductive tract antimicrobial peptides HE2alpha and HE2beta2 act synergistically with the commonly used antibiotics to inhibit E. coli growth. A combination of HE2alpha and HE2beta2 peptides resulted in an additive effect. Interestingly, the synergistic effects of HE2 peptides were highest with doxycycline and ciprofloxacin, antibiotics generally used to treat epididymitis. Results of this study demonstrate the potential of endogenous HE2 peptides to be pharmacologically important in designing novel strategies to treat reproductive tract infections.

In VitroandIn VivoSynergistic Effects of Cryptdin 2 and Ampicillin against Salmonella

“…The fractional bactericidal concentration (FBC) was calculated by dividing the MBC of the combination of cryptdin 2 and Amp by the MBC of cryptdin 2 or Amp alone. The FBC index, obtained by adding both FBCs, was interpreted as indicating a synergistic effect when it was Յ0.5, an additive or indifferent effect when it was Ͼ0.5 and Յ2.0, and an antagonistic effect when it was Ͼ2.0 (42).…”

“…Combination therapy with antibiotics and defensins can therefore be used to increase the in vivo activity as well as to broaden the antimicrobial spectrum (13). Earlier, several AMPs were used in combination with conventional drugs against various bacteria, fungi, and viruses (10,16,21,31,42). However, until now, to the best of our knowledge, no information has been available on the combined activity of cryptdins and conventional anti-Salmonella drugs.…”

Efficacy of Cryptdin-2 as an Adjunct to Antibiotics from Various Generations Against Salmonella

“…To evaluate synergy, the fractional inhibitory concentration (FIC) index was determined by checkerboard microtitre test, using an 8-by-8 well configuration at 64 different combinations as described earlier [15,17]. Briefly, twofold serial dilutions of cryptdin-2 and each antibiotic were prepared, with concentrations ranging from 0.016 to 2 times the MBC.…”

“…The FBC index, obtained by adding both FBCs, was interpreted as indicating a synergistic effect when it was B0.5, an additive or indifferent effect when it was [0.5 and B2.0 and an antagonistic effect when it was [2.0 [15].…”

“…This is due to the scarcity of antibiotics compared with the huge diversity of demanding clinical care scenarios currently encountered in antimicrobial therapy [13]. Earlier, the combinations of AMPs and conventional drugs have been successfully employed to overcome antibiotic resistance in selected cases [13][14][15]. Recently, we demonstrated that cryptdin-2 possesses a strong in vivo therapeutic potential against murine salmonellosis and it can be used as a possible adjunct to ampicillin for superior treatment of salmonellosis [16,17].…”