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The rapid emergence of antimicrobial resistance in Acinetobacter baumannii coupled with the dried pipeline of novel treatments has driven the search for new therapeutic modalities. Gram-negative bacteria have an extra outer membrane that serves as a permeability barrier for various hydrophobic and/or large compounds. One of the popular approaches to tackle this penetration barrier is use of potentiators or adjuvants in combination with traditional antibiotics. This study reports the in vitro potential of an antimicrobial peptide tridecaptin M in combination with other antibiotics against different strains of A. baumannii. Tridecaptin M sensitized the bacteria to rifampicin, vancomycin, and ceftazidime. Further, we observed that a tridecaptin M and rifampicin combination killed the bacteria completely in 4 h in an ex vivo blood infection model and was superior to rifampicin monotherapy. The study also found that concomitant administration of both compounds is not necessary to achieve the antimicrobial effect. Bacteria pre-treated with tridecaptin M (for 2–4 h) followed by exposure to rifampicin showed similar killing as obtained for combined treatment. Additionally, this combination hampered the survival of persister development in comparison to rifampicin alone. These findings encourage the future investigation of this combination to treat severe infections caused by extremely drug-resistant A. baumannii.

Efflux pumps of the resistance-nodulation-cell division (RND) superfamily, particularly the AcrAB-TolC, and MexAB-OprM, besides mediating intrinsic and acquired resistance, also intervene in bacterial pathogenicity. Inhibitors of such pumps could restore the activities of antibiotics and curb bacterial virulence. Here, we identify pyrrole-based compounds that boost antibiotic activity in Escherichia coli and Pseudomonas aeruginosa by inhibiting their archetype RND transporters. Molecular docking and biophysical studies revealed that the EPIs bind to AcrB. The identified efflux pump inhibitors (EPIs) inhibit the efflux of fluorescent probes, attenuate persister formation, extend post-antibiotic effect, and diminish resistant mutant development. The bacterial membranes remained intact upon exposure to the EPIs. EPIs also possess an anti-pathogenic potential and attenuate P . aeruginosa virulence in vivo . The intracellular invasion of E . coli and P . aeruginosa inside the macrophages was hampered upon treatment with the lead EPI. The excellent efficacy of the EPI-antibiotic combination was evidenced in animal lung infection and sepsis protection models. These findings indicate that EPIs discovered herein with negligible toxicity are potential antibiotic adjuvants to address life-threatening Gram-negative bacterial infections.

Background: Drug delivery against ciprofloxacin-resistant microbial strains is one of the most challenging areas of research in the pharmaceutical industry. The broad-spectrum antibiotic ciprofloxacin often faces challenges due to its poor bioavailability; thus, the activity of this drug is generally compromised against resistant strains. Traditional drug delivery systems, such as liposomes, are utilized to address this issue; however, niosomes have surfaced as a promising successor to their liposomal counterparts due to their superior attributes, such as enhanced stability and reduced toxicity. However, owing to environmental and toxicological concerns over commonly used chemical surfactants in niosomes, there is a pressing need to explore greener and safer alternatives. This study is focused on the application of sophorolipids (SLs), a biosurfactant that is synthesized by the yeast Starmerella bombicola, as a vesicular assembly for ciprofloxacin encapsulation. Methods: The SL-based niosomal formulation was characterized for particle size, zeta potential, and polydispersity index (PDI), while transmission electron microscopy (TEM) was employed to determine the morphology of niosomes. Agar well diffusion, broth dilution, and biofilm inhibition assays were performed to assess efficacy. Results: The niosomal formulations were successfully prepared; among them, the (+)vely charged formulation exhibited a more organized morphology, and their size and zeta potential values were found to be around ~371 nm and 63 mV for the blank niosomes (without the loaded drug) and ~269 nm and 51 mV for the ciprofloxacin-loaded niosomes. The minimum inhibitory concentration and biofilm inhibitory concentration against the MRSA strain were 5 µg/mL and 25 µg/mL, respectively, for the ciprofloxacin-loaded, (+)vely charged SL niosomes—for free ciprofloxacin these values were 40 µg/mL and 100 µg/mL—presenting remarkable potential for biofilm inhibition. Conclusion: This study highlights the promising therapeutic potential of SL-based ciprofloxacin-loaded niosomes against the emerging health threat of the MRSA strain.

Antibiotic-resistance is ever growing burden on our society for the past many years. Many synthetic chemistry approaches and rational drug-design have been unable to pace up and tackle this problem. Natural resources, more specifically, the microbial diversity, on the other hand, make a traditional and still the best platform to search for new chemical scaffolds and compounds. Here, we report the antimicrobial characteristics of novel bacterial isolate from a salt lake in India. We screened the bacterial isolates for their inhibitory activity against indicator bacteria and found that four novel species were able to prevent the growth of test strains studied in vitro . Further, we characterized one novel species (SMB1 T  = SL4-2) using polyphasic taxonomic approaches and also purified the active ingredient from this bacterium. We successfully characterized the antimicrobial compound using mass spectroscopy and amino acid analysis. We also allocated two novel biosynthetic gene clusters for putative bacteriocins and one novel non-ribosomal peptide gene cluster in its whole genome. We concluded that the strain SMB1 T belonged to the genus Paenibacilllus with the pairwise sequence similarity of 98.67% with Paenibacillus tarimensis DSM 19409 T and we proposed the name Paenibacillus sambharensis sp. nov. The type strain is SMB1 T (=MTCC 12884 = KCTC 33895 T ).

Background: Staphylococcus aureus is a highly lethal Gram-positive bacterium that is responsible for over one million deaths annually. As a member of the ESKAPE pathogens, its methicillin-resistant strains (MRSA) are prevalent worldwide and exhibit significant antimicrobial resistance (AMR). Bacterial efflux pumps play a pivotal role in the development of AMR by facilitating the expulsion of a range of antimicrobial agents. Methods: The S. aureus strain SA-1199B, which overexpresses NorA and carries a GrlA mutation, was utilized to comprehensively profile the mechanism of the compounds PQQ16P and PQK4F. To assess the toxicity and genotoxicity of these compounds, RAW macrophages, HEK 293T, and HepG2 cell lines were utilized. Female BALB/c mice were utilized to assess the in vivo synergism of EPIs with CPX, Results: NorA efflux pump inhibitors (EPIs), PQQ16P and PQK4F, enhanced the efficacy of the antibacterial ciprofloxacin (CPX) against resistant S. aureus strains. The mechanism of EPIs involved the inhibition of NorA efflux pump, without compromising bacterial membrane permeability, ATP levels, or mammalian calcium channels. Moreover, the EPIs significantly augmented the bactericidal and post-antibiotic effects of CPX, elevating its mutation prevention concentration without manifesting substantial toxicity to human cells. Furthermore, the EPIs reduced S. aureus invasiveness in macrophages, indicating a role for NorA in bacterial virulence. Notably, the in vivo synergism of these EPIs with CPX was observed in a mouse infection model. Conclusions: This study provides substantial evidence for the potential of employing EPIs in a combination with CPX to counteract AMR, both in vitro and in vivo.

Extensive usage of antibiotics has led to the emergence of drug-resistant strains of pathogens and hence, there is an urgent need for alternative antimicrobial agents. Antimicrobial Peptides (AMPs) of bacterial origin have shown the potential to replace some conventional antibiotics. In the present study, an AMP was isolated from Bacillus subtilis subsp. spizizenii strain Ba49 present on the Allium cepa, the common onion and named as peptide-Ba49. The isolated AMP was purified and characterized. The purified peptide-Ba49, having a molecular weight of ~ 3.3 kDa as determined using mass spectroscopy, was stable up to 121 °C and in the pH range of 5–10. Its interaction with protein degrading enzymes confirmed the peptide nature of the molecule. The peptide exhibited low minimum inhibitory concentration (MIC) against Staphylococcus aureus and its (Methicillin-resistant Staphylococcus aureus) MRSA strains (MIC, 2–16 µM/mL). Further, time kill kinetic assay was performed and analysis of the results of membrane depolarization and permeabilization assays (TEM, DiBAC4 (3) and PI) suggested peptide-Ba49 to be acting through the change in membrane potential leading to disruption of S. aureus membrane. Additionally, cytotoxicity studies of peptide-Ba49, carried out using three mammalian cell lines viz. HEK 293T, RAW 264.7, and L929, showed limited cytotoxicity on these cell lines at a concentration much higher than its MIC values. All these studies suggested that the AMP isolated from strain Ba49 (peptide-Ba49) has the potential to be an alternative to antibiotics in terms of eradicating the pathogenic as well as drug-resistant microorganisms.

The survival of modern medicine depends heavily on the effective prevention and treatment of bacterial infections, are threatened by antibacterial resistance. The increasing use of antibiotics and lack of stewardship have led to an increase in antibiotic-resistant pathogens, so the growing issue of resistance can be resolved by emphasizing chemically synthesized antibiotics. This study discovered SMJ-2, a synthetic indole derivative, is effective against all multidrug-resistant gram-positive bacteria. SMJ-2 has multiple targets of action, but the primary mechanism inhibits respiratory metabolism and membrane potential disruption. SMJ-2 was discovered to interfere with the mevalonate pathway, ultimately preventing the synthesis of farnesyl diphosphate, a precursor to the antioxidant staphyloxanthin, eventually releasing reactive oxygen species, and leading phagocytic cells to destroy pathogens. Additionally, no discernible biochemical and histopathological alterations were found in the mouse acute toxicity model. This study emphasizes mechanistic insights into SMJ-2 as a potential antibacterial with an unusual method of action. Synthetic indole derivative kills gram-positive bacteria by quenching the respiratory metabolism pathway.

Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium responsible for several infections in humans. The infections caused by this bacterial strain are difficult to treat due to the resistance of MRSA to clinically used antibiotics. Several medicinal plants extracts and their phytoconstituents have been reported to possess modulation and efflux pump inhibitory (EPI) activity against MRSA strains. Alpinia calcarata rhizomes have been reported to be used in Ayurveda for several ailments including fungal infections. Based on this information and in continuation with our efforts to discover EPIs from Indian medicinal plants, we describe EPI activity of flavonoids isolated from A. calcarata. Galangin and kaempferol showed ≥ 32-fold modulation in minimum inhibitory concentration (MIC) of ethidium bromide (EtBr) as well as norfloxacin in NorA-overexpressed S. aureus (SA-1199B) strain. Pinocembrin showed 32-fold modulation of EtBr MIC in SA-1199 strain, but not in SA-1199B and K1758 strains. A significant diference was not observed in the modulation of norfloxacin MIC by galangin in SA-1199 and SA-1199B strains, which may be due to non-specific nature of galangin as modulator or EPI. However, kaempferol modulated the MIC of EtBr as well as norfloxacin 64-fold and 32-fold, respectively. Also, the best modulatory effect of kaempferol was observed only in SA-1199B strain compared to two other strains. The EPI activity of kaempferol and galangin were found to be competitive with respect to verapamil. In dose-response assay, kaempferol at 31.25 μg/mL concentration was found to be better EPI by inhibiting NorA pump in SA-1199B strain and also demonstrated further confocal microscopy.

Probiotic industries strive for new, efficient and promising probiotic strains that impart a positive impact on consumer health. Challenges are persisting in isolation, screening, and selection of the new indigenous probiotic strains. In the present research, we explored the probiotic potential of 17 lactic acid bacteria isolated from Yak milk in a series of in vitro tests. We also demonstrated their health benefits, i.e., cholesterol degradation, lactose digestion, antimicrobial activity, antioxidant, and anticancer activities. Principal component analysis revealed that more than 50% of the strains fulfilled the examined criteria, e.g., survival in acidic pH, bile concentrations, and adherent property. Approximately all the strains produced antimicrobial substances against the maximum number of tested strains including clinical strains. Most strains degraded cholesterol in comparison to the reference probiotic strain whereas strain Yc showed 1.5 times higher the degradation efficiency of the control strain. Lan4 strain exhibited remarkable anticancer activity and induced the maximum apoptosis (87%) in the Hela cells and was non-toxic to the non-cancerous HEK293 cells. Around ten strains showed positive lactose digestion. Overall, this can be concluded that selected lactic acid bacteria revealed excellent probiotic properties along with desirable health benefits. These strains need to be further investigated in details for their application in the development of novel probiotic preparations for the improvement of public health.