Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline.
Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline.
复制标题
乌干达恶性疟原虫分离株对抗疟药物管道的敏感性。
DOI：
10.1128/spectrum.05236-22
复制
发表时间：
2023-06-15
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
疟疾，特别是恶性疟原虫感染，仍然是一个巨大的问题，其治疗和控制受到耐药性的严重挑战。需要新的抗疟疾药物。为了描述正在开发的抗疟疾药物风险管道中的药物，我们评估了2015-2022年收集的998株恶性疟原虫临床分离株对19种化合物的体外敏感性，这些化合物针对恶性疟原虫ABC转运蛋白I家族成员1、乙酰-CoA合成酶、细胞色素b、二氢罗酸脱氢酶、延伸因子2、赖氨酰-tRNA合成酶、苯丙氨酰-tRNA合成酶、纤溶酶X、前药物激活和抗药性酯酶以及V型H+ATPase突变。用SYBR Green进行72h生长抑制试验(半数抑制浓度[IC50])测定药物敏感性。现场分离株对铅抗疟药高度敏感，所有受试化合物的低至中纳摩尔IC50中值接近先前报告的实验室菌株的值。然而，发现了易感性降低的异常值。对于具有共同目标的化合物，IC50结果之间存在正相关。我们对编码假定靶标的基因进行了测序，以表征序列多样性，搜索先前用体外药物压力选择的多态，并确定基因与表型的相关性。我们在靶基因中发现了许多多态，通常在10%的分离株中，但没有一个是先前在体外选择的那些有药物压力的基因，也没有一个与显著降低体外药物敏感性有关。总体而言，乌干达恶性疟原虫分离株对作为下一代抗疟疾药物的19种化合物高度敏感，这与乌干达循环寄生虫中缺乏先前存在的或新的导致耐药性的突变是一致的。重要的是抗药性需要开发新的抗疟疾药物。重要的是评估正在开发的化合物对目前在非洲引起疾病的寄生虫的活性，并确定这些寄生虫的突变是否会限制新药物的疗效。我们发现，非洲分离株通常对所研究的19种铅抗疟药高度敏感。对推测的药物靶标进行测序发现了这些基因中的多个突变，但这些突变通常与抗疟疾活性降低无关。这些结果使人们相信，目前正在开发的经过测试的抗疟疾化合物的活性不会受到非洲疟疾寄生虫先前存在的抗药性中介突变的限制。
Malaria, especially Plasmodium falciparum infection, remains an enormous problem, and its treatment and control are seriously challenged by drug resistance. New antimalarial drugs are needed. To characterize the Medicines for Malaria Venture pipeline of antimalarials under development, we assessed the ex vivo drug susceptibilities to 19 compounds targeting or potentially impacted by mutations in P. falciparum ABC transporter I family member 1, acetyl-CoA synthetase, cytochrome b, dihydroorotate dehydrogenase, elongation factor 2, lysyl-tRNA synthetase, phenylalanyl-tRNA synthetase, plasmepsin X, prodrug activation and resistance esterase, and V-type H+ ATPase of 998 fresh P. falciparum clinical isolates collected in eastern Uganda from 2015 to 2022. Drug susceptibilities were assessed by 72-h growth inhibition (half-maximum inhibitory concentration [IC50]) assays using SYBR green. Field isolates were highly susceptible to lead antimalarials, with low- to midnanomolar median IC50s, near values previously reported for laboratory strains, for all tested compounds. However, outliers with decreased susceptibilities were identified. Positive correlations between IC50 results were seen for compounds with shared targets. We sequenced genes encoding presumed targets to characterize sequence diversity, search for polymorphisms previously selected with in vitro drug pressure, and determine genotype-phenotype associations. We identified many polymorphisms in target genes, generally in <10% of isolates, but none were those previously selected in vitro with drug pressure, and none were associated with significantly decreased ex vivo drug susceptibility. Overall, Ugandan P. falciparum isolates were highly susceptible to 19 compounds under development as next-generation antimalarials, consistent with a lack of preexisting or novel resistance-conferring mutations in circulating Ugandan parasites. IMPORTANCE Drug resistance necessitates the development of new antimalarial drugs. It is important to assess the activities of compounds under development against parasites now causing disease in Africa, where most malaria cases occur, and to determine if mutations in these parasites may limit the efficacies of new agents. We found that African isolates were generally highly susceptible to the 19 studied lead antimalarials. Sequencing of the presumed drug targets identified multiple mutations in these genes, but these mutations were generally not associated with decreased antimalarial activity. These results offer confidence that the activities of the tested antimalarial compounds now under development will not be limited by preexisting resistance-mediating mutations in African malaria parasites.
登录
查看更多内容
DOI：
10.1093/infdis/jiy223
发表时间：
2018-08-14
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Aydemir O;Janko M;Hathaway NJ;Verity R;Mwandagalirwa MK;Tshefu AK;Tessema SK;Marsh PW;Tran A;Reimonn T;Ghani AC;Ghansah A;Juliano JJ;Greenhouse BR;Emch M;Meshnick SR;Bailey JA
通讯作者：
Bailey JA
影响因子：
64.8
作者：
Kato N;Comer E;Sakata-Kato T;Sharma A;Sharma M;Maetani M;Bastien J;Brancucci NM;Bittker JA;Corey V;Clarke D;Derbyshire ER;Dornan GL;Duffy S;Eckley S;Itoe MA;Koolen KM;Lewis TA;Lui PS;Lukens AK;Lund E;March S;Meibalan E;Meier BC;McPhail JA;Mitasev B;Moss EL;Sayes M;Van Gessel Y;Wawer MJ;Yoshinaga T;Zeeman AM;Avery VM;Bhatia SN;Burke JE;Catteruccia F;Clardy JC;Clemons PA;Dechering KJ;Duvall JR;Foley MA;Gusovsky F;Kocken CH;Marti M;Morningstar ML;Munoz B;Neafsey DE;Sharma A;Winzeler EA;Wirth DF;Scherer CA;Schreiber SL
通讯作者：
Schreiber SL
影响因子：
3.9
作者：
Dhorda M;Amaratunga C;Dondorp AM
通讯作者：
Dondorp AM
柬埔寨恶性疟原虫疟疾中的双氢青蒿素-哌喹抗药性：一项多地点前瞻性队列研究。
DOI：
10.1016/s1473-3099(15)00487-9
发表时间：
2016-03
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
Amaratunga C;Lim P;Suon S;Sreng S;Mao S;Sopha C;Sam B;Dek D;Try V;Amato R;Blessborn D;Song L;Tullo GS;Fay MP;Anderson JM;Tarning J;Fairhurst RM
通讯作者：
Fairhurst RM
影响因子：
4.8
作者：
Cobbold, Simon A.;Vaughan, Ashley M.;Llinas, Manuel
通讯作者：
Llinas, Manuel