The small molecule IITR08027 restores the antibacterial activity of fluoroquinolones against multidrug-resistant Acinetobacter baumannii by efflux inhibition

Bhattacharyya, Tapas; Sharma, Atin; Akhter, Jawed; Pathania, Ranjana

doi:10.1016/j.ijantimicag.2017.03.005

Cited by 53 publications

(35 citation statements)

References 28 publications

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“…The BM1122 from RP-HPLC was concentrated and applied to measurement of MIC value as described method (Bhattacharyya et al, 2017 ) in 96 well plate (Costar, Corning, USA). S. aureus ATCC 29213 and E. coli ATCC 25922 were used as indicators.…”

Section: Methodsmentioning

confidence: 99%

Efficient Exploitation of Multiple Novel Bacteriocins by Combination of Complete Genome and Peptidome

Luo

Lü

2018

Front. Microbiol.

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Backgroud: The growing emergence of antibiotic-resistant pathogens including the most dangerous superbugs requires quick discovery of novel antibiotics/biopreservatives for human health and food safety. Bacteriocins, a subgroup of antimicrobial peptides, have been considered as promising alternatives to antibiotics. Abundant novel bacteriocins are stored in genome sequences of lactic acid bacteria. However, discovery of novel bacteriocins still mainly relies on dubious traditional purification with low efficiency. Moreover, sequence alignment is invalid for novel bacteriocins which have no homology to known bacteriocins in databases. Therefore, an efficient, simple, universal, and time-saving method was needed to discover novel bacteriocins.Methods and Results: Crude bacteriocins from both cell-related and culture supernatant of Lactobacillus crustorum MN047 fermentation were applied to LC-MS/MS for peptidome assay, by which 131 extracellular peptides or proteins were identified in the complete genome sequence of L. crustorum MN047. Further, the genes of suspected bacteriocins were verified by expressed in Escherichia coli BL21 (DE3) pLysS. Thereafter, eight novel bacteriocins and two nonribosomal antimicrobial peptides were identified to be broad-spectrum activity against both Gram-positive and Gram-negative bacteria, including some multidrug-resistant strains. Among them, BM1556 located within predicted bacteriocin gene cluster. The most active bacteriocin BM1122 had low MIC values of 13.7 mg/L against both Staphylococcus aureus ATCC29213 and E. coli ATCC25922. The BM1122 had bactericidal action mode by biofilm-destruction, pore-formation, and membrane permeability change.Conclusions: The combination of complete genome and peptidome is a valid approach for quick discovery of novel bacteriocins without/with-low homology to known ones. This method will contribute to deep exploitation of novel bacteriocins in genome of bacteria submitted to GenBank.

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Section: Methodsmentioning

confidence: 99%

Efficient Exploitation of Multiple Novel Bacteriocins by Combination of Complete Genome and Peptidome

Luo

Lü

2018

Front. Microbiol.

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“…The enhanced sensitivity toward fluoroquinolones was linked to the inhibition of proton gradient and multidrug efflux pump, AbeM. IITR08027 at a concentration of 25 µM decreased the MIC values of several antibiotics to significant levels, extended the post-antibiotic effect, and minimized resistant mutant selection ( 298 ). Such new strategies hold promise in minimizing and reversing the phenomenon of multidrug resistance, besides increasing the life of antibiotic.…”

Section: Other Recent Developmentsmentioning

confidence: 99%

Antimicrobial Resistance: Its Surveillance, Impact, and Alternative Management Strategies in Dairy Animals

et al. 2018

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Antimicrobial resistance (AMR), one among the most common priority areas identified by both national and international agencies, is mushrooming as a silent pandemic. The advancement in public health care through introduction of antibiotics against infectious agents is now being threatened by global development of multidrug-resistant strains. These strains are product of both continuous evolution and un-checked antimicrobial usage (AMU). Though antibiotic application in livestock has largely contributed toward health and productivity, it has also played significant role in evolution of resistant strains. Although, a significant emphasis has been given to AMR in humans, trends in animals, on other hand, are not much emphasized. Dairy farming involves surplus use of antibiotics as prophylactic and growth promoting agents. This non-therapeutic application of antibiotics, their dosage, and withdrawal period needs to be re-evaluated and rationally defined. A dairy animal also poses a serious risk of transmission of resistant strains to humans and environment. Outlining the scope of the problem is necessary for formulating and monitoring an active response to AMR. Effective and commendably connected surveillance programs at multidisciplinary level can contribute to better understand and minimize the emergence of resistance. Besides, it requires a renewed emphasis on investments into research for finding alternate, safe, cost effective, and innovative strategies, parallel to discovery of new antibiotics. Nevertheless, numerous direct or indirect novel approaches based on host–microbial interaction and molecular mechanisms of pathogens are also being developed and corroborated by researchers to combat the threat of resistance. This review places a concerted effort to club the current outline of AMU and AMR in dairy animals; ongoing global surveillance and monitoring programs; its impact at animal human interface; and strategies for combating resistance with an extensive overview on possible alternates to current day antibiotics that could be implemented in livestock sector.

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“…Unfortunately, this drawback seems to apply to most EPI development, with no inhibitors successfully completing clinical trials to date. Recently, a promising small molecule inhibitor (IITR8027, Figure 2 ) of proton driven A. baumannii efflux pumps has re-sensitised MDR bacteria to ciprofloxacin, despite displaying no antibacterial activity on its own [ 134 ]. Additionally, IITRR8027 showed no cytotoxicity at the reported minimum effective concentration for ciprofloxacin potentiation [ 134 ].…”

Section: Efflux Pumpsmentioning

confidence: 99%

“…Recently, a promising small molecule inhibitor (IITR8027, Figure 2 ) of proton driven A. baumannii efflux pumps has re-sensitised MDR bacteria to ciprofloxacin, despite displaying no antibacterial activity on its own [ 134 ]. Additionally, IITRR8027 showed no cytotoxicity at the reported minimum effective concentration for ciprofloxacin potentiation [ 134 ]. The novel pyranopyradine inhibitor MBX2319 ( Figure 2 ) has been shown to potentiate current antibiotics through inhibition of the AcrAB efflux pump in E. coli ; however, the lack of potency and stability were major drawbacks [ 135 ].…”

Section: Efflux Pumpsmentioning

confidence: 99%

Overcoming Intrinsic and Acquired Resistance Mechanisms Associated with the Cell Wall of Gram-Negative Bacteria

et al. 2020

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The global increase in multi-drug-resistant bacteria is severely impacting our ability to effectively treat common infections. For Gram-negative bacteria, their intrinsic and acquired resistance mechanisms are heightened by their unique cell wall structure. The cell wall, while being a target of some antibiotics, represents a barrier due to the inability of most antibacterial compounds to traverse and reach their intended target. This means that its composition and resulting mechanisms of resistance must be considered when developing new therapies. Here, we discuss potential antibiotic targets within the most well-characterised resistance mechanisms associated with the cell wall in Gram-negative bacteria, including the outer membrane structure, porins and efflux pumps. We also provide a timely update on the current progress of inhibitor development in these areas. Such compounds could represent new avenues for drug discovery as well as adjuvant therapy to help us overcome antibiotic resistance.

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The small molecule IITR08027 restores the antibacterial activity of fluoroquinolones against multidrug-resistant Acinetobacter baumannii by efflux inhibition

Cited by 53 publications

References 28 publications

Efficient Exploitation of Multiple Novel Bacteriocins by Combination of Complete Genome and Peptidome

Efficient Exploitation of Multiple Novel Bacteriocins by Combination of Complete Genome and Peptidome

Antimicrobial Resistance: Its Surveillance, Impact, and Alternative Management Strategies in Dairy Animals

Overcoming Intrinsic and Acquired Resistance Mechanisms Associated with the Cell Wall of Gram-Negative Bacteria

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