Review of recent innovations in portable child growth measurement devices for use in low- and middle-income countries

Acknowledgements: We would like to thank Ulster University colleagues, Professor John Anthony Byrne (principal investigator for the SAFEWATER project), Ms Vanessa Ross (SAFEWATER Project Manager) and Ms Anna Zmuda-Trzebiatowska (Global Grants Development Manager) for their guidance and support throughout the project. We are grateful to all the growth measurement device developers for sharing their product information with us. The authors accept full responsibility for this paper and have no competing interests. Funding The authors wish to acknowledge funding from the Department of Economy, The Global Challenges Research Fund (GCRF) Internal Pump Priming Call, in turn building upon a much larger GCRF, UK Research and Innovation grant for the SAFEWATER project (EPSRC Grant Reference EP/P032427/1).Peer reviewedPublisher PD

Atomic modelling and systematic mutagenesis identify residues in multiple drug binding sites that are essential for drug resistance in the major Candida transporter Cdr1

International audienceThe ABC (ATP-Binding Cassette) transporter Cdr1 (Candida drug resistance 1) protein (Cdr1p) of Candida albicans, shows promiscuity towards the substrate it exports and plays a major role in antifungal resistance. It has two transmembrane domains (TMDs) comprising of six transmembrane helices (TMH) that envisage and confer the substrate specificity and two nucleotide binding domains (NBDs), interconnected by extracellular loops (ECLs) and intracellular loops (ICLs) Cdr1p. This study explores the diverse substrate specificity spectrum to get a deeper insight into the structural and functional features of Cdr1p. By screening with the variety of compounds towards an in-house TMH 252 mutant library of Cdr1p, we establish new substrates of Cdr1p. The localization of substrate-susceptible mutants in an ABCG5/G8 homology model highlights the common and specific binding pockets inside the membrane domain, where rhodamines and tetrazoliums mainly engage the N-moiety of Cdr1p, binding between TMH 2, 11 and surrounded by TMH 1, 5. Whereas, tin chlorides involve both N and C moieties located at the interface of TMH 2, 11, 1 and 5. Further, screening of the in house TMH mutant library of Cdr1p displays the TMH12 interaction with tetrazolium chloride, trimethyltin chloride and a Ca 2+ ionophore, A23187. In silico localization reveals a binding site at the TMH 12, 9 and 10 interface, which is widely exposed to the lipid interface. Together, for the first time, our study shows the molecular localization of Cdr1p substrates-binding sites and demonstrates the participation of TMH12 in a peripheral drug binding site

Evaluation of Jatrophane Esters from <i>Euphorbia</i> spp. as Modulators of <i>Candida albicans</i> Multidrug Transporters

Twenty-nine jatrophane esters (<b>1</b>–<b>10</b>, <b>12</b>–<b>30</b>) and one lathyrane (<b>11</b>) diterpenoid ester isolated from <i>Euphorbia</i> species were evaluated for their capacity to inhibit drug-efflux activities of the primary ABC transporter CaCdr1p and the secondary MFS transporter CaMdr1p of <i>Candida albicans</i>, in yeast strains overexpressing the corresponding transporter. These diterpenoid esters were obtained from <i>Euphorbia semiperfoliata</i> (<b>1</b>–<b>10</b>), <i>E. insularis</i> (<b>11</b>), and <i>E. dendroides</i> (<b>12</b>–<b>30</b>) and included five new compounds, euphodendroidins P–T (<b>26</b>–<b>30</b>). The jatrophane esters <b>12</b> and <b>23</b> were found to inhibit the efflux of Nile Red (NR) mediated by the two multidrug transporters, at 85–64% for CaCdr1p and 79–65% for CaMdr1p. In contrast, compound <b>21</b> was selective for CaCdr1p and induced a strong inhibition (92%), whereas compound <b>8</b> was selective for CaMdr1p, with a 74% inhibition. It was demonstrated further that potency and selectivity are sensitive to the substitution pattern on the jatrophane skeleton. However, these compounds were not transported and showed no synergism with fluconazole cytotoxicity