Antimycobacterial activity of cyclic dipeptides isolated fromBacillussp. N strain associated with entomopathogenic nematode

Abstract

Context: Tuberculosis (TB) is one of the leading causes of morbidity and mortality with a global mortality rate of two million deaths per year; one-third of the world's population is infected with Mycobacterium tuberculosis. Objective: The aim of this study was to determine the antimycobacterial activity of six diketopiperazines (DKPs) purified from a Bacillus sp. N strain associated with entomopathogenic nematode Rhabditis (Oscheius) sp. Materials and methods: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration of DKPs were determined using the broth dilution method on Middlebrook 7H11 against M. tuberculosis H 37 Rv. Time-kill assay was used to determine the rate of killing of M. tuberculosis H 37 Rv by DKPs. The cytotoxicity of the DKPs was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay against the VERO cell line. Results: Out of six DKP-tested cyclo-(D-Pro-L-Leu), cyclo-(L-Pro-L-Met) and cyclo-(D-Pro-L-Phe)recorded antimycobacterial activity, the cyclo-(L-Pro-L-Met) showed the highest activity and MIC values of 4 mg/ml for M. tuberculosis H 37 Rv. The MIC value for rifampicin was 0.06 mg/ml. Growth curve study by the MIC concentration of cyclic dipeptides recorded significant inhibition when compared with control. Time-kill curve showed maximum reduction of colony count was between 3 and 5 weeks. The DKPs are nontoxic to the VERO cell line up to 200 mg/ml. The antimycobacterial activity of cyclo-(D-Pro-L-Leu), cyclo-(L-Pro-L-Met) and cyclo-(D-Pro-L-Phe) is reported in this study for the first time. Discussion and conclusion: In conclusion, the potency, low cytotoxicity and selectivity of these compounds make them valid lead compounds for treatment against TB.

Profiling of Potential Antibacterial Compounds of Lactic Acid Bacteria against Extremely Drug Resistant (XDR) Acinetobacter baumannii

“…The high binding of CDPs to microbial membrane receptors such as OMP exerts a radical scavenging effect and an overall antagonistic effect against various biological cells including pathogenic bacteria, viruses, fungi, and tumors. These properties predominate as an attractive model for drug design [22][23][24]. The inhibition mechanism of CDPs could be due to their hydrophobic nature, which could interfere with the bacterial cell membrane, influencing their function and loss of cell integrity, causing cell death [25].…”

“…The compound, 3-Isobutyl-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione is also known as cyclo (D-Pro-L-Leu) or cyclo (L-Pro-D-Leu). Antimicrobial activity of 3-Isobutyl-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione has been widely reported against Candida albicans with minimum inhibitory concentration (MIC) of 16 µg/mL and minimum fungicidal concentration (MFC) of 32 µg/mL [24]; Aspergillus flavus and Aspergillus niger with MIC of 8 µg/mL and 32 µg/mL, respectively, which are 500-fold and 156-fold lower compared to the control [26]; Mycobacterium tuberculosis with MIC of 8 µg/mL and minimum bactericidal concentration (MBC) of 16 µg/mL [23]; Vibro anguillarum with MIC of 0.13 µg/mL, which was about four times lower than oxytetracycline (0.5 µg/mL) [27]. Pyrrolo(2,1-F)pyrazine-1,4-d-one,2,3,6,7,8,8A-hexahydro-3-(phenylmethyl)-is also known as cyclo (D-Phe-L-Pro).…”

A cyclic dipeptide for salinity stress alleviation and the trophic flexibility of an endophyte reveal niches in salt marsh plant-microbe interactions

“…These CDPs could be classified into proline-(includes hydroxyproline) and non-prolinebased groups and nine were observed only under the NaCl-present condition (Table S6). CDPs have been reported as biostimulants against biotic and abiotic stresses in plants (31)(32)(33)(34)(35), and many proline-and hydroxyproline-based CDPs were patented in inducing resistance in plants against abiotic stresses (36). However, our understanding of those non-proline-based CDPs and their roles in MPMI remains limited.…”

“…In previous studies, we isolated endophytic strains from various natural habitats and used them to construct synthetic plant-endophyte symbiosis systems for plant cultivation under biotic or abiotic stress conditions (5,(23)(24)(25)(26). On the other hand, some specific metabolites, such as pyrroloquinoline quinone (PQQ) and cyclodipeptides (CDPs), have been identified as potential biostimulants (23,(27)(28)(29)(30), while some CDPs were also reported as agricultural agents that could protect crops against biotic and abiotic stresses (31)(32)(33)(34)(35). Although some of them had been patented for applications more than three decades ago (36), the molecular bases of the role of cyclodipeptides in moderating plant stresses and in plant-microbe interactions remain to be elucidated.…”