Alternatives to Conventional Antibiotics in the Era of Antimicrobial Resistance

Ghosh, Chandradhish; Sarkar, Paramita; Issa, Rahaf; Haldar, Jayanta

doi:10.1016/j.tim.2018.12.010

Cited by 536 publications

(436 citation statements)

References 122 publications

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“…There is a trend towards reducing the complexity of faecal transplants by controlling the transfer of bacterial strains or selecting natural strains derived from a healthy microbiota 59,60 . New techniques based on synthetic biology and systems biology allow the precise genetic engineering of well-known probiotics 61 , which may also express specific antibacterial substances [62][63][64] . A long-known strategy to maintain a healthy microbiota is the use of antibiotic inactivators or absorbers of bacterial toxins in the gut.…”

Section: Compassionate Usementioning

confidence: 99%

The global preclinical antibacterial pipeline

Theuretzbacher¹,

et al. 2019

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| Antibacterial resistance is a great concern and requires global action. A critical question is whether enough new antibacterial drugs are being discovered and developed. A review of the clinical antibacterial drug pipeline was recently published, but comprehensive information about the global preclinical pipeline is unavailable. This Review focuses on discovery and preclinical development projects and has found, as of 1 May 2019, 407 antibacterial projects from 314 institutions. The focus is on Gram-negative pathogens, particularly bacteria on the WHO priority bacteria list. The preclinical pipeline is characterized by high levels of diversity and interesting scientific concepts, with 135 projects on direct-acting small molecules that represent new classes, new targets or new mechanisms of action. There is also a strong trend towards non-traditional approaches, including diverse antivirulence approaches, microbiome-modifying strategies, and engineered phages and probiotics. The high number of pathogen-specific and adjunctive approaches is unprecedented in antibiotic history. Translational hurdles are not adequately addressed yet, especially development pathways to show clinical impact of nontraditional approaches. The innovative potential of the preclinical pipeline compared with the clinical pipeline is encouraging but fragile. Much more work , focus and funding are needed for the novel approaches to result in effective antibacterial therapies to sustainably combat antibacterial resistance.

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Section: Compassionate Usementioning

confidence: 99%

The global preclinical antibacterial pipeline

Theuretzbacher¹,

et al. 2019

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“…Increasing rates of antibiotic resistance among Gram-negative pathogens such as Pseudomonas aeruginosa represent a serious risk to worldwide health (1,2). The prevalence of multi-drug-resistant (MDR) strains capable to inactivating a broad array of antibiotics has stimulated the development of alternative therapies (3)(4)(5). Bacteriocins produced by P. aeruginosa, termed pyocins, represent an emerging antimicrobial option for the treatment of infections caused by MDR strains (6,7).…”

Section: Introductionmentioning

confidence: 99%

Structural and functional analysis of pyocin S8 fromPseudomonas aeruginosa: requirement of a glutamate in the H-N-H motif for the DNase activity

Turano

Fomes

Domingos

et al. 2020

Preprint

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Multi-drug resistance (MDR) is a serious threat to global public health, making the development of new antimicrobials an urgent necessity. Pyocins are protein antibiotics produced by Pseudomonas aeruginosa strains to kill closely related cells during intraspecific competition. Here, we report an in depth biochemical, microbicidal and structural characterization of a new S-type pyocin, named S8. Initially, we described the domain organization and secondary structure of S8. Subsequently, we observed that a recombinant S8 composed of the killing subunit in complex with the immunity (Im) protein killed the strain PAO1. Furthermore, mutation of a highly conserved glutamic acid to alanine (Glu100Ala) completely inhibited this antimicrobial activity. Probably the integrity of the H-N-H motif is essential in the killing activity of S8, as Glu100 is a highly conserved component of this structure. Next, we observed that S8 is a metal-dependent endonuclease, as EDTA treatment abolished its ability to cleave supercoiled pUC18 plasmid. Supplementation of apo S8 with Ni 2+ strongly induced this DNase activity, whereas Mn 2+ and Mg 2+ exhibited moderate effects and Zn 2+ was inhibitory. Additionally, S8 bound Zn 2+ with a higher affinity than Ni 2+ and the Glu100Ala mutation decreased the affinity of S8 for these metals as shown by isothermal titration calorimetry (ITC). Finally, we describe the crystal structure of the Glu100Ala pyocin-S8DNase-Im complex at 1.38 Å, which gave us new insights into the endonuclease activity of S8. Our results reinforce the possible use of S8 as an alternative antibiotic for MDR Pseudomonas aeruginosa strains, while leaving commensal human microbiota intact.

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“…; Gosh et al . in press). Although their application in Eastern Europe is well documented (Merabishvili et al .…”

Section: Introductionmentioning

confidence: 99%

Antibiofilm potential of purified environmental bacteriophage preparations against early stage Pseudomonas aeruginosa biofilms

et al. 2019

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Aims This paper presents the potential of environmentally sourced bacteriophages to affect the growth of clinical isolates of Pseudomonas aeruginosa biofilms, and assesses the respective plaque morphotypes presented by each bacteriophage, in vitro. Methods and Results Bacterial host strains were typed for their ability to produce the quorum sensing‐controlled virulence factor pyocyanin, and then tested for bacteriophage susceptibility using the spot test method. The bacteriophages were co‐administered with ciprofloxacin in order to determine whether the bacteriophages would demonstrate synergistic or antagonistic behaviour to the antibiotic in vitro. Results suggest a potential relationship between the bacteriophage plaque size and biofilm inhibition, where those producing smaller plaques appear to be more effective at reducing bacterial biofilm formation. Conclusions This phenomenon may be explained by a high adsorption rate leading to the rapid formation of smaller plaques, and greater biofilm reduction associated with the loss of viable bacterial cells before the cells can adhere to the surface and form a biofilm. Results from the co‐administration of bacteriophage and ciprofloxacin suggest that the two work synergistically to affect P. aeruginosa biofilms. Significance and Impact of the Study The data indicate enhanced efficacy of ciprofloxacin by ≥50%. This could offer an alternative strategy for targeting antibiotic‐resistant infections.

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Alternatives to Conventional Antibiotics in the Era of Antimicrobial Resistance

Cited by 536 publications

References 122 publications

The global preclinical antibacterial pipeline

The global preclinical antibacterial pipeline

Structural and functional analysis of pyocin S8 fromPseudomonas aeruginosa: requirement of a glutamate in the H-N-H motif for the DNase activity

Antibiofilm potential of purified environmental bacteriophage preparations against early stage Pseudomonas aeruginosa biofilms

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