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A broad spectrum anti-bacterial peptide with an adjunct potential for tuberculosis chemotherapy.

ABSTRACT: Alternative ways to prevent and treat infectious diseases are needed. Previously, we identified a fungal peptide, NZX, that was comparable to rifampicin in lowering M. tuberculosis load in a murine tuberculosis (TB) infection model. Here we assessed the potential synergy between this cationic host defence peptide (CHDP) and the current TB drugs and analysed its pharmacokinetics. We found additive effect of this peptide with isoniazid and ethambutol and confirmed these results with ethambutol in a murine TB-model. In vivo, the peptide remained stable in circulation and preserved lung structure better than ethambutol alone. Antibiotic resistance studies did not induce mutants with reduced susceptibility to the peptide. We further observed that this peptide was effective against nontuberculous mycobacteria (NTM), such as M. avium and M. abscessus, and several Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. In conclusion, the presented data supports a role for this CHDP in the treatment of drug resistant organisms.

SUBMITTER: Rao KU

PROVIDER: S-EPMC7892554 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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A broad spectrum anti-bacterial peptide with an adjunct potential for tuberculosis chemotherapy.

Rao Komal Umashankar KU Henderson Domhnall Iain DI Krishnan Nitya N Puthia Manoj M Glegola-Madejska Izabela I Brive Lena L Bjarnemark Fanny F Millqvist Fureby Anna A Hjort Karin K Andersson Dan I DI Tenland Erik E Sturegård Erik E Robertson Brian D BD Godaly Gabriela G

Scientific reports 20210218 1

Alternative ways to prevent and treat infectious diseases are needed. Previously, we identified a fungal peptide, NZX, that was comparable to rifampicin in lowering M. tuberculosis load in a murine tuberculosis (TB) infection model. Here we assessed the potential synergy between this cationic host defence peptide (CHDP) and the current TB drugs and analysed its pharmacokinetics. We found additive effect of this peptide with isoniazid and ethambutol and confirmed these results with ethambutol in ...[more]

PMID: 33603037

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Project description:Bacteria form multicellular communities known as biofilms that cause two thirds of all infections and demonstrate a 10 to 1000 fold increase in adaptive resistance to conventional antibiotics. Currently, there are no approved drugs that specifically target bacterial biofilms. Here we identified a potent anti-biofilm peptide 1018 that worked by blocking (p)ppGpp, an important signal in biofilm development. At concentrations that did not affect planktonic growth, peptide treatment completely prevented biofilm formation and led to the eradication of mature biofilms in representative strains of both Gram-negative and Gram-positive bacterial pathogens including Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, methicillin resistant Staphylococcus aureus, Salmonella Typhimurium and Burkholderia cenocepacia. Low levels of the peptide led to biofilm dispersal, while higher doses triggered biofilm cell death. We hypothesized that the peptide acted to inhibit a common stress response in target species, and that the stringent response, mediating (p)ppGpp synthesis through the enzymes RelA and SpoT, was targeted. Consistent with this, increasing (p)ppGpp synthesis by addition of serine hydroxamate or over-expression of relA led to reduced susceptibility to the peptide. Furthermore, relA and spoT mutations blocking production of (p)ppGpp replicated the effects of the peptide, leading to a reduction of biofilm formation in the four tested target species. Also, eliminating (p)ppGpp expression after two days of biofilm growth by removal of arabinose from a strain expressing relA behind an arabinose-inducible promoter, reciprocated the effect of peptide added at the same time, leading to loss of biofilm. NMR and chromatography studies showed that the peptide acted on cells to cause degradation of (p)ppGpp within 30 minutes, and in vitro directly interacted with ppGpp. We thus propose that 1018 targets (p)ppGpp and marks it for degradation in cells. Targeting (p)ppGpp represents a new approach against biofilm-related drug resistance.

Project description:The urgent need for new antibacterial drugs arises from the emergence of bacterial multidrug resistance due to antibiotic overuse. Antimicrobial peptides, crucial components of innate immunity in animals and plants, exhibit effectiveness against multidrug-resistant bacteria while minimizing the development of drug resistance. In this study, the antibacterial peptide BsR1, comprising 21 amino acids, was finalized by predicting the active site of an antifungal gene and sequence optimization. BsR1 displayed broad-spectrum antibacterial activities against diverse Gram-positive and Gram-negative bacteria, with a low minimum inhibitory concentration of 4.25-17 μM. Stability experiments demonstrated that BsR1 has high resistance to thermal, ultraviolet, and acid-base conditions, while revealing increased sensitivity to divalent ions Ca2+ and Mg2+. The mode of action of BsR1 involved cell membrane damage, leading to bacterial cell structure disruption and subsequent death. Secondary structure prediction indicated a linear helical conformation with a positive charge of +7.5, facilitating its interaction with the target cell membrane. BsR1 exhibited excellent biological safety, as it did not induce necrosis in tobacco leaves, and the low observed hemolytic effect on mammalian cells with a value of 3.26%. Additionally, BsR1 demonstrated the ability to enhance disease resistance in rice and effectively curbed the spread of rice bacterial blight. This research presents BsR1 as a novel approach and potential medication in the development of antibacterial drugs, offering a valuable tool in combating pathogenic microorganisms, particularly in plants.IMPORTANCEThis study addresses the critical need for new antibacterial drugs in the face of bacterial multidrug resistance resulting from antibiotic overuse. It highlights the significance of antimicrobial peptides as essential components of innate immunity in animals and plants, which have been proven effective against multidrug-resistant bacteria and are difficult to develop resistance against. This study successfully synthesizes a broad-spectrum antibacterial peptide, BsR1, with strong inhibitory activities against various Gram-positive and Gram-negative bacteria. BsR1 demonstrates favorable stability and a mode of action that damages bacterial cell membranes, leading to cell death. It also exhibits biological safety and shows potential in enhancing disease resistance in rice. This research offers a novel approach and potential medication for antibacterial drug development, presenting a valuable tool in combating pathogenic microorganisms, particularly in plants.

Dataset Information

A broad spectrum anti-bacterial peptide with an adjunct potential for tuberculosis chemotherapy.

Publications

A broad spectrum anti-bacterial peptide with an adjunct potential for tuberculosis chemotherapy.

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