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Antimicrobial peptide novicidin synergizes with rifampin, ceftriaxone, and ceftazidime against antibiotic-resistant EnterobacteriaceaeIn Vitro

Antimicrobial peptide novicidin synergizes with rifampin, ceftriaxone, and ceftazidime against antibiotic-resistant EnterobacteriaceaeIn Vitro
Antimicrobial peptide novicidin synergizes with rifampin, ceftriaxone, and ceftazidime against antibiotic-resistant EnterobacteriaceaeIn Vitro
The spread of antibiotic resistance among Gram-negative bacteria is a serious clinical threat, and infections with these organisms are a leading cause of mortality worldwide. Traditional novel drug development inevitably leads to the emergence of new resistant strains, rendering the new drugs ineffective. Therefore, reviving the therapeutic potentials of existing antibiotics represents an attractive novel strategy. Novicidin, a novel cationic antimicrobial peptide, is effective against Gram-negative bacteria. Here, we investigated novicidin as a possible antibiotic enhancer. The actions of novicidin in combination with rifampin, ceftriaxone, or ceftazidime were investigated against 94 antibiotic-resistant clinical Gram-negative isolates and 7 strains expressing New Delhi metallo-?-lactamase-1. Using the checkerboard method, novicidin combined with rifampin showed synergy with >70% of the strains, reducing the MICs significantly. The combination of novicidin with ceftriaxone or ceftazidime was synergistic against 89.7% of the ceftriaxone-resistant strains and 94.1% of the ceftazidime-resistant strains. Synergistic interactions were confirmed using time-kill studies with multiple strains. Furthermore, novicidin increased the postantibiotic effect when combined with rifampin or ceftriaxone. Membrane depolarization assays revealed that novicidin alters the cytoplasmic membrane potential of Gram-negative bacteria. In vitro toxicology tests showed novicidin to have low hemolytic activity and no detrimental effect on cell cultures. We demonstrated that novicidin strongly rejuvenates the therapeutic potencies of ceftriaxone or ceftazidime against resistant Gram-negative bacteria in vitro. In addition, novicidin boosted the activity of rifampin. This strategy can have major clinical implications in our fight against antibiotic-resistant bacterial infections.
0066-4804
6233-6240
Soren, Odel
fbec1ab5-90ed-4515-a164-b374b0930a26
Brinch, Karoline Sidelmann
27101352-ed84-4b98-a301-96b256352a31
Patel, Dipesh
3e6011a2-12c8-4cf8-be4b-11a5fdfe9a96
Liu, Yingjun
e9c4ef2c-afec-4e16-978b-a57d09bb09d9
Liu, Alexander
b8ac4400-c286-4844-87db-8819c467de91
Coates, Anthony
8da8cc51-fab0-401b-b860-ab6456589a29
Hu, Yanmin
1ec1b062-4c43-4e47-a4fa-caacc5b4bcaf
Soren, Odel
fbec1ab5-90ed-4515-a164-b374b0930a26
Brinch, Karoline Sidelmann
27101352-ed84-4b98-a301-96b256352a31
Patel, Dipesh
3e6011a2-12c8-4cf8-be4b-11a5fdfe9a96
Liu, Yingjun
e9c4ef2c-afec-4e16-978b-a57d09bb09d9
Liu, Alexander
b8ac4400-c286-4844-87db-8819c467de91
Coates, Anthony
8da8cc51-fab0-401b-b860-ab6456589a29
Hu, Yanmin
1ec1b062-4c43-4e47-a4fa-caacc5b4bcaf

Soren, Odel, Brinch, Karoline Sidelmann, Patel, Dipesh, Liu, Yingjun, Liu, Alexander, Coates, Anthony and Hu, Yanmin (2015) Antimicrobial peptide novicidin synergizes with rifampin, ceftriaxone, and ceftazidime against antibiotic-resistant EnterobacteriaceaeIn Vitro. Antimicrobial Agents and Chemotherapy, 59 (10), 6233-6240. (doi:10.1128/AAC.01245-15). (PMID:26248380)

Record type: Article

Abstract

The spread of antibiotic resistance among Gram-negative bacteria is a serious clinical threat, and infections with these organisms are a leading cause of mortality worldwide. Traditional novel drug development inevitably leads to the emergence of new resistant strains, rendering the new drugs ineffective. Therefore, reviving the therapeutic potentials of existing antibiotics represents an attractive novel strategy. Novicidin, a novel cationic antimicrobial peptide, is effective against Gram-negative bacteria. Here, we investigated novicidin as a possible antibiotic enhancer. The actions of novicidin in combination with rifampin, ceftriaxone, or ceftazidime were investigated against 94 antibiotic-resistant clinical Gram-negative isolates and 7 strains expressing New Delhi metallo-?-lactamase-1. Using the checkerboard method, novicidin combined with rifampin showed synergy with >70% of the strains, reducing the MICs significantly. The combination of novicidin with ceftriaxone or ceftazidime was synergistic against 89.7% of the ceftriaxone-resistant strains and 94.1% of the ceftazidime-resistant strains. Synergistic interactions were confirmed using time-kill studies with multiple strains. Furthermore, novicidin increased the postantibiotic effect when combined with rifampin or ceftriaxone. Membrane depolarization assays revealed that novicidin alters the cytoplasmic membrane potential of Gram-negative bacteria. In vitro toxicology tests showed novicidin to have low hemolytic activity and no detrimental effect on cell cultures. We demonstrated that novicidin strongly rejuvenates the therapeutic potencies of ceftriaxone or ceftazidime against resistant Gram-negative bacteria in vitro. In addition, novicidin boosted the activity of rifampin. This strategy can have major clinical implications in our fight against antibiotic-resistant bacterial infections.

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Accepted/In Press date: 18 July 2015
e-pub ahead of print date: 27 July 2015
Published date: October 2015
Organisations: Biomedicine

Identifiers

Local EPrints ID: 388552
URI: https://eprints.soton.ac.uk/id/eprint/388552
ISSN: 0066-4804
PURE UUID: f8611143-0db4-4c2a-8c31-24201ed88617

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Date deposited: 29 Feb 2016 14:16
Last modified: 28 Aug 2019 18:31

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