Computational resources in the management of antibiotic resistance: speeding up drug discovery

For over four decades structural biology has been used to understand the mechanisms of disease, and structure-guided approaches have demonstrated clearly that they can contribute to many aspects of early drug discovery, both computationally and experimentally. Structure can also inform our understanding of impacts of mutations in human genetic diseases and drug resistance in cancers and infectious diseases. We discuss the ways that structural insights might be useful in both repurposing off-licence drugs and guide the design of new molecules that might be less susceptible to drug resistance in the future.

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Translational control of antibiotic resistance

Open Biology ◽

10.1098/rsob.190051 ◽

2019 ◽

Vol 9 (7) ◽

pp. 190051 ◽

Cited By ~ 1

Author(s):

Anne Witzky ◽

Rodney Tollerson ◽

Michael Ibba

Keyword(s):

Antibiotic Resistance ◽

Drug Discovery ◽

Translational Control ◽

Treatment Options ◽

Mechanisms Of Resistance ◽

Translation Elongation ◽

The Past ◽

New Treatment ◽

Bacterial Translation ◽

Ribosomal Protection

Many antibiotics available in the clinic today directly inhibit bacterial translation. Despite the past success of such drugs, their efficacy is diminishing with the spread of antibiotic resistance. Through the use of ribosomal modifications, ribosomal protection proteins, translation elongation factors and mistranslation, many pathogens are able to establish resistance to common therapeutics. However, current efforts in drug discovery are focused on overcoming these obstacles through the modification or discovery of new treatment options. Here, we provide an overview for common mechanisms of resistance to translation-targeting drugs and summarize several important breakthroughs in recent drug development.

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Synergy between Indoloquinolines and Ciprofloxacin: An Antibiofilm Strategy against Pseudomonas aeruginosa

Antibiotics ◽

10.3390/antibiotics10101205 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1205

Author(s):

Emilie Charpentier ◽

Ludovic Doudet ◽

Ingrid Allart-Simon ◽

Marius Colin ◽

Sophie C. Gangloff ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Antimicrobial Activity ◽

Antibiotic Resistance ◽

Drug Discovery ◽

Crystal Violet ◽

Biofilm Formation ◽

Bacterial Biofilm ◽

Quinoline Derivatives ◽

Crystal Violet Staining ◽

Radical Process

Antibiotic treatments can participate in the formation of bacterial biofilm in case of under dosage. The interest of indoloquinoline scaffold for drug discovery incited us to study the preparation of new indolo [2,3-b]quinoline derivatives by a domino radical process. We tested the effect of two different “indoloquinoline” molecules (Indol-1 and Indol-2) without antimicrobial activity, in addition to ciprofloxacin, on biofilm formation thanks to crystal violet staining and enumeration of adhered bacteria. This association of ciprofloxacin and Indol-1 or Indol-2 attenuated the formation of biofilm up to almost 80% compared to ciprofloxacin alone, or even prevented the presence of adhered bacteria. In conclusion, these data prove that the association of non-antimicrobial molecules with an antibiotic can be a solution to fight against biofilm and antibiotic resistance emergence.

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An Overview of the Treatment Options Used for the Management of COVID-19 in Pakistan: Retrospective Observational Study (Preprint)

10.2196/preprints.28594 ◽

2021 ◽

Author(s):

Hashaam Akhtar ◽

Samar Akhtar ◽

Fazal-Ul Rahman ◽

Maham Afridi ◽

Sundas Khalid ◽

...

Keyword(s):

Antibiotic Resistance ◽

Drug Discovery ◽

Observational Study ◽

Treatment Options ◽

Tertiary Care ◽

Multidrug Resistant ◽

Retrospective Observational Study ◽

Immunocompromised Patients ◽

First Line ◽

Tertiary Care Hospitals

BACKGROUND Since the first reports of COVID-19 infection, the foremost requirement has been to identify a treatment regimen that not only fights the causative agent but also controls the associated complications of the infection. Due to the time-consuming process of drug discovery, physicians have used readily available drugs and therapies for treatment of infections to minimize the death toll. OBJECTIVE The aim of this study is to provide a snapshot analysis of the major drugs used in a cohort of 1562 Pakistani patients during the period from May to July 2020, when the first wave of COVID-19 peaked in Pakistan. METHODS A retrospective observational study was performed to provide an overview of the major drugs used in a cohort of 1562 patients with COVID-19 admitted to the four major tertiary-care hospitals in the Rawalpindi-Islamabad region of Pakistan during the peak of the first wave of COVID-19 in the country (May-July 2020). RESULTS Antibiotics were the most common choice out of all the therapies employed, and they were used as first line of treatment for COVID-19. Azithromycin was the most prescribed drug for treatment. No monthly trend was observed in the choice of antibiotics, and these drugs appeared to be a random but favored choice throughout the months of the study. It was also noted that even antibiotics used for multidrug resistant infections were prescribed irrespective of the severity or progression of the infection. The results of the analysis are alarming, as this approach may lead to antibiotic resistance and complications in immunocompromised patients with COVID-19. A total of 1562 patients (1064 male, 68.1%, and 498 female, 31.9%) with a mean age of 47.35 years (SD 17.03) were included in the study. The highest frequency of patient hospitalizations occurred in June (846/1562, 54.2%). CONCLUSIONS Guidelines for a targeted treatment regime are needed to control related complications and to limit the misuse of antibiotics in the management of COVID-19.

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Sampling the Antibiotic Resistome

Science ◽

10.1126/science.1120800 ◽

2006 ◽

Vol 311 (5759) ◽

pp. 374-377 ◽

Cited By ~ 872

Author(s):

Vanessa M. D'Costa ◽

Katherine M. McGrann ◽

Donald W. Hughes ◽

Gerard D. Wright

Keyword(s):

Antibiotic Resistance ◽

Microbial Community ◽

Drug Discovery ◽

Early Warning ◽

Early Warning System ◽

Warning System ◽

Resistance Mechanisms ◽

Community Study ◽

Synthetic Compounds ◽

Resistance Determinants

Microbial resistance to antibiotics currently spans all known classes of natural and synthetic compounds. It has not only hindered our treatment of infections but also dramatically reshaped drug discovery, yet its origins have not been systematically studied. Soil-dwelling bacteria produce and encounter a myriad of antibiotics, evolving corresponding sensing and evading strategies. They are a reservoir of resistance determinants that can be mobilized into the microbial community. Study of this reservoir could provide an early warning system for future clinically relevant antibiotic resistance mechanisms.

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Novel therapeutics for bacterial infections

Emerging Topics in Life Sciences ◽

10.1042/etls20160017 ◽

2017 ◽

Vol 1 (1) ◽

pp. 85-92 ◽

Cited By ~ 1

Author(s):

Peter W. Taylor

Keyword(s):

Antibiotic Resistance ◽

Drug Discovery ◽

Bacterial Infections ◽

Bacterial Pathogens ◽

Novel Therapeutics ◽

The Past ◽

Encoded Proteins ◽

New Antibiotics ◽

Marked Decline

The relentless increase in antibiotic resistance among all major groups of bacterial pathogens shows no sign of abating. The situation is exacerbated by a marked decline in the number of new antibiotics entering the marketplace. It is essential that new ways to treat severe bacterial infections are investigated before the antibiotic well runs dry. This review covers many promising approaches, some novel and some based on old ideas that were not considered viable when clinicians were able to exploit a wide palette of cheap and effective antibacterial chemotherapeutics. These approaches include the use of photosensitive dyes, bacteriophage and phage-encoded proteins, and agents that compromise virulence and antibiotic-resistance machineries. I also make a case for continuing in some form with tried and trusted platforms for drug discovery that served society well in the past.

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