Substrate-Envelope-Guided Design of Drugs with a High Barrier to the Evolution of Resistance

Introduction. Treatment of Haemophilus influenzae (Hi) pneumonia is on concern because resistance to amoxicillin is largely diffused. This study describes the evolution of resistance to amoxicillin and amoxicillin/clavulanic acid (AMC) in Hi isolates and characteristics of patients with Hi severe pneumonia. Methods. A monocentric retrospective observational study including patients from 2008 to 2017 with severe pneumonia hospitalized in ICU. Evolution of amoxicillin and AMC susceptibility was showed. Characteristics of patients with Hi pneumonia were compared to characteristics of patients with Streptococcus pneumoniae (Sp) pneumonia, as reference. Risk factors for amoxicillin resistance in Hi were investigated. Results. Overall, 113 patients with Hi and 132 with Sp pneumonia were included. The percentages of AMC resistance among Hi strains decreased over the years (from 10% in 2008-2009 to 0% in 2016-2017) while resistance to amoxicillin remained stable at 20%. Also, percentages of Sp resistant strains for amoxicillin decreased over years (from 25% to 3%). Patients with Hi pneumonia experienced higher prevalence of bronchitis (18% vs. 8%, p=0.02, chronic obstructive pulmonary disease (43% vs. 30% p=0.03), HAP (18% vs. 7%, p=0.01, ventilator-associated pneumonia (27% vs. 17%, p=0.04, and longer duration of mechanical ventilation (8 days vs. 6 days, p=0.04) than patients with Sp pneumonia. Patients with Sp pneumonia had more frequently local complications than patients with Hi pneumonia (17% vs. 7%, p=0.03). De-escalation of antibiotics was more frequent in patients with Sp than in patients with Hi (67% vs. 53%, p=0.03). No risk factors were associated with amoxicillin resistance among patients with Hi pneumonia. Conclusions. Amoxicillin resistance was stable over time, but no risk factors were detected. AMC resistance was extremely low, suggesting that AMC could be used for empiric treatment of Hi pneumonia, as well as other molecules, namely, cephalosporins. Patients with Hi pneumonia had more pulmonary comorbidities and severe diseases than patients with Sp pneumonia.

Download Full-text

Molecular pathways to high-level azithromycin resistance in Neisseria gonorrhoeae

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkab084 ◽

2021 ◽

Cited By ~ 1

Author(s):

J G E Laumen ◽

S S Manoharan-Basil ◽

E Verhoeven ◽

S Abdellati ◽

I De Baetselier ◽

...

Keyword(s):

Neisseria Gonorrhoeae ◽

Ribosomal Proteins ◽

Efflux Pump ◽

23S Rrna ◽

Rrna Gene ◽

23S Rrna Gene ◽

Evolution Of Resistance ◽

High Level ◽

Azithromycin Resistance ◽

Level Resistance

Abstract Background The prevalence of azithromycin resistance in Neisseria gonorrhoeae is increasing in numerous populations worldwide. Objectives To characterize the genetic pathways leading to high-level azithromycin resistance. Methods A customized morbidostat was used to subject two N. gonorrhoeae reference strains (WHO-F and WHO-X) to dynamically sustained azithromycin pressure. We tracked stepwise evolution of resistance by whole genome sequencing. Results Within 26 days, all cultures evolved high-level azithromycin resistance. Typically, the first step towards resistance was found in transitory mutations in genes rplD, rplV and rpmH (encoding the ribosomal proteins L4, L22 and L34 respectively), followed by mutations in the MtrCDE-encoded efflux pump and the 23S rRNA gene. Low- to high-level resistance was associated with mutations in the ribosomal proteins and MtrCDE efflux pump. However, high-level resistance was consistently associated with mutations in the 23S ribosomal RNA, mainly the well-known A2059G and C2611T mutations, but also at position A2058G. Conclusions This study enabled us to track previously reported mutations and identify novel mutations in ribosomal proteins (L4, L22 and L34) that may play a role in the genesis of azithromycin resistance in N. gonorrhoeae.

Download Full-text

Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance

Chemistry & Biology ◽

10.1016/j.chembiol.2013.07.014 ◽

2013 ◽

Vol 20 (9) ◽

pp. 1116-1124 ◽

Cited By ~ 36

Author(s):

Madhavi N.L. Nalam ◽

Akbar Ali ◽

G.S. Kiran Kumar Reddy ◽

Hong Cao ◽

Saima G. Anjum ◽

...

Keyword(s):

Drug Resistance ◽

Protease Inhibitors ◽

Hiv 1 ◽

Substrate Envelope

Download Full-text

Global patterns in genomic diversity underpinning the evolution of insecticide resistance in the aphid crop pest Myzus persicae

Communications Biology ◽

10.1038/s42003-021-02373-x ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Kumar Saurabh Singh ◽

Erick M. G. Cordeiro ◽

Bartlomiej J. Troczka ◽

Adam Pym ◽

Joanna Mackisack ◽

...

Keyword(s):

Host Plant ◽

Myzus Persicae ◽

Resistance Mechanisms ◽

Genomic Diversity ◽

Resistance Mutations ◽

Host Plant Adaptation ◽

Repeated Evolution ◽

Evolution Of Resistance ◽

Selective Forces ◽

Clonal Lines

AbstractThe aphid Myzus persicae is a destructive agricultural pest that displays an exceptional ability to develop resistance to both natural and synthetic insecticides. To investigate the evolution of resistance in this species we generated a chromosome-scale genome assembly and living panel of >110 fully sequenced globally sampled clonal lines. Our analyses reveal a remarkable diversity of resistance mutations segregating in global populations of M. persicae. We show that the emergence and spread of these mechanisms is influenced by host–plant associations, uncovering the widespread co‐option of a host-plant adaptation that also offers resistance against synthetic insecticides. We identify both the repeated evolution of independent resistance mutations at the same locus, and multiple instances of the evolution of novel resistance mechanisms against key insecticides. Our findings provide fundamental insights into the genomic responses of global insect populations to strong selective forces, and hold practical relevance for the control of pests and parasites.

Download Full-text