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Antimicrobials: Discovery, clinical use, and development of resistance

Preprints that describe the discovery of new antimicrobials and any improvements made regarding their clinical use. Includes preprints that detail the factors affecting antimicrobial selection and the development of antimicrobial resistance.

List by Zhang-He Goh

Preprints:

Antibiotic concentrations in the sinonasal secretions and tissue in CRS patients after oral therapy: a randomized trial

Joey Siu, Lilian Klingler, Yi Wang, Cheung-Tak Hung, Soo Hee Jeong, Susan Smith, Malcolm Tingle, Brett Mackenzie, Kristi Biswas, Richard G Douglas

https://www.biorxiv.org/content/10.1101/2020.06.17.158535v1

Siu et al. determined the sinonasal concentrations of doxycycline and roxithromycin, antibiotics which are commonly used in the treatment of chronic rhinosinusitis. They found that these concentrations tended to be significantly lower than the minimum inhibitory concentration (MIC) of pathogens commonly associated with acute sinusitis and upper respiratory infection. These results suggest that the poor penetration of these antibiotics into sinonasal secretions may limit their efficacy in treating chronic rhinosinusitis.

Selection for antibiotic resistance is reduced when embedded in a natural microbial community

Uli Klümper, Mario Recker, Lihong Zhang, Xiaole Yin, Tong Zhang, Angus Buckling, William Gaze

https://www.biorxiv.org/content/10.1101/529651v1

The overuse of antibiotics in both medicine and agriculture, especially in the latter, has led to a drastic rise in antibiotic resistance over the last decade. Notably, the rise of antibiotic resistance has been so meteoric that it is now listed as one of the World Health Organisation (WHO) has listed as “one of the biggest threats to global health, food security, and development today”. In their preprint, Klumper et al. explored the ecological factors that affect the development of antimicrobial resistance in a microbial community.

Contribution of pretomanid to novel regimens containing bedaquiline with either linezolid or moxifloxacin and pyrazinamide in murine models of tuberculosis

Jian Xu, Si-Yang Li, Deepak V. Almeida, Rokeya Tasneen, Kala Barnes-Boyle, Paul J. Converse, Anna M. Upton, Khisimuzi Mdluli, Nader Fotouhi, Eric L. Nuermberger

https://www.biorxiv.org/content/10.1101/514661v1

As recently as 2018, the World Health Organisation described Multidrug-resistant TB (MDR-TB) as “a public health crisis and a health security threat”. This urgency necessitates the development of drug regimens to reduce resistance, as well as the discovery of drugs with new mechanisms of action. In their preprint, Xu et al. described tests of a combination of antitubercular drugs, including pretomanid, in three different murine models: nude mice, BALB/c mice, and C3HeB/FeJ mice.

Estimation of Pharmacokinetic Parameters of Continuous Intravenous Flucloxacillin infusion in the Outpatient Settings (PKFLUCLOX)

N Lwin, Z Liu, M Loewenthal, P Dobson, JW Yoo, P Galettis, K Lai, J Martin

https://www.biorxiv.org/content/10.1101/499848v1

Lwin et al. characterise the pharmacokinetics of intravenously-administered flucloxacillin and develop a model to aid in outpatient administration of flucloxacillin.

Biological Evaluation of Molecules of the azaBINOL Class as Antiviral Agents: Specific Inhibition of HIV-1 RNase H Activity by 7-Isopropoxy-8-(naphth-1-yl)quinoline

Ross D Overacker, Somdev Banerjee, George F Neuhaus, Selena Milicevic Sephton, Alexander Herrmann, James A Strother, Ruth Brack-Werner, Paul R Blakemore, Sandra Loesgen

https://www.biorxiv.org/content/10.1101/525105v1

Plant and marine sources of drugs have traditionally been favoured as a source for inspiration of drugs. Inspired by bioactive biaryl-containing natural products from these sources, Overacker et al. screen a library of these compounds for their their antiviral activity.

Targeting extracellular glycans: Tuning multimeric boronic acids for pathogen-selective killing of Mycobacterium tuberculosis

Collette S Guy, Matthew I Gibson, Elizabeth Fullam

https://www.biorxiv.org/content/10.1101/529743v1

Guy et al. report a class of multimeric boronic acids which kill Mycobacterium tuberculosis (Mtb)by binding specifically to the glycans on the Mtb cell envelope. In doing so, the authors demonstrate how future antitubercular drug discovery may involve new mechanisms of action which target unique extracellular components on Mtb.

Epidemiology of Staphylococcus aureus in Neonates on Admission to a Chinese Neonatal Intensive Care Unit

Wenjing Geng, Yujie Qi, Wenting Li, Thomas H McConvillle, Alexandra Hill Ricciuti, Emily Grohs, Lisa Saiman, Anne-Catrin Uhlemann

https://www.biorxiv.org/content/10.1101/529941v1

By identifying risk factors for nasal colonisation and transmission of Staphylococcus aureus in neonates admitted to a Chinese Neonatal Intensive Care Unit, Geng et al. contribute findings which support the need to actively monitor neonates for S. aureus to better control the spread of methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA).

Amoxicillin inactivation by thiol-catalyzed cyclization reduces protein haptenation and antibacterial potency

María A. Pajares, Tahl Zimmerman, Francisco J. Sánchez-Gómez, Adriana Ariza, María J. Torres, Miguel Blanca, F. Javier Cañada, María I. Montañez, Dolores Pérez-Sala

https://www.biorxiv.org/content/10.1101/647966v1

In their preprint, Pajares et al. investigate the factors that determine amoxicillin bioavailability. The authors reinforce past research that amoxicillin bioavailability is indeed affected by redox status, and highlight the possibility that amoxicillin may interact with thiol-containing compounds.

Antimalarial drug mefloquine kills both trophozoite and cyst stages of Entamoeba Mefloquine and Entamoeba histolytica

Conall Sauvey, Gretchen Ehrenkaufer, Anjan Debnath, Ruben Abagyan

https://www.biorxiv.org/content/10.1101/501999v1

This preprint by Sauvey et al. reinforces the value in drug repurposing; specifically, it reminds us that even old drugs with considerable side effects can still be useful in the context of other infectious diseases.

Development and validation of serological markers for detecting recent exposure to Plasmodium vivax infection

Rhea J. Longley, Michael T. White, Eizo Takashima, Jessica Brewster, Masayuki Morita, Matthias Harbers, Leanne J. Robinson, Fumie Matsuura, Shih-Jung Zoe Liu, Connie S. N. Li-Wai-Suen, Wai-Hong Tham, Julie Healer, Christele Huon, Chetan E. Chitnis, Wang Nguitragool, Wuelton Monteiro, Carla Proietti, Denise L. Doolan, Xavier C. Ding, Iveth J. Gonzalez, James Kazura, Marcus Lacerda, Jetsumon Sattabongkot, Takafumi Tsuboi, Ivo Mueller

https://www.biorxiv.org/content/10.1101/481168v1

This preprint by Longley et al. underscores the role that big data plays in the world of infectious diseases. Indeed, amassing large amounts of data helps not just in drug discovery, but also in accelerating the development of diagnostic tests that are simultaneously more sensitive and specific, as well as more rapid and inexpensive.

Combining antibiotics with antivirulence compounds is effective and can reverse selection for antibiotic resistance in Pseudomonas aeruginosa

Chiara Rezzoagli, Martina Archetti, Michael Baumgartner, Rolf Kümmerli

https://www.biorxiv.org/content/10.1101/861799v1

Rezzoagli  et al. investigate the effectiveness of combinations of anti-virulence compounds and antibiotics in mitigating the resistance of Pseudomonas aeruginosa to existing antibiotics. Full preLight available here.

Identification of two aptamers binding to Legionella pneumophila with high affinity and specificity

Mariam Saad, Deanna Chinerman, Maryam Tabrizian, Sebastien P. Faucher

https://www.biorxiv.org/content/10.1101/2019.12.13.875476v1

Using the Systemic Evolution of Ligands through EXponential enrichment (SELEX), Saad et al. identify two aptamers that bind to Legionella pneumophila (LP) with high affinity and specificity. The preprint authors envision that these aptamers may be further developed into tests to detect LP in water samples.

The spread of chloramphenicol-resistant Neisseria meningitidis in Southeast Asia

Elizabeth M Batty, Tomas-Paul Cusack, Janjira Thaipadungpanit, Wanitda Watthanaworawit, Verena Carrara, Somsavanh Sihalath, Jill Hopkins, Sona Soeng, Clare Ling, Paul Turner, David A. B. Dance

https://www.biorxiv.org/content/10.1101/2019.12.13.872499v1

Batty et al. apply whole-genome sequencing clinical isolates from 18 patients (specifically, from Cambodia, Thailand, and Laos) to characterise the spread of chloramphenicol-resistant Neisseria meningitidis in Southeast Asia.

Schistosomes alter expression of immunomodulatory gene products following in vivo praziquantel exposure

Paul McCusker, Claudia M Rohr, John D Chan

https://www.biorxiv.org/content/10.1101/2020.01.22.915710v1

McCusker et al. investigate the in vivo mechanisms of action of praziquantel (PZQ), an anti-schistosomiasis agent, and its effects on Schistosoma mansoni. Specifically, the authors investigated the in vivo effects of  sublethal PZQ concentrations on the S. mansoni transcriptomes. One of their key findings–that PZQ significantly upregulated Kunitz-type protease inhibitors, such as SmKI-1–support current efforts in the development of schistosomiasis vaccine targets, and may also aid in the identification of new targets for schistosomiasis treatment.

In Vivo Efficacy and PK/PD Modeling of KBP-7072, An Aminomethylcycline Antibiotic, in Neutropenic Pneumonia and Thigh Infection Models

Xiaojuan Tan, Min Zhang, Qingmei Liu, Ping Wang, Tian Zhou, Vincent Benn, Fred Yang

https://www.biorxiv.org/content/10.1101/2020.03.18.998112v1

Using a murine pneumonia model, Tan et al. characterise the in vivo antibacterial activity of KBP-7072 against bacteria that cause community-acquired pneumonia. They also characterise the pharmacokinetic-pharmacodynamic relationship of KBP-7072’s bactericidal activity using a murine thigh-infection model.

Categories: bioinformatics , clinical trials , epidemiology , immunology , microbiology , pharmacology and toxicology , synthetic biology

 

Posted on: 21st May 2019 , updated on: 21st June 2020

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