Khayat Maan T, Abbas Hisham A, Ibrahim Tarek S, Khayyat Ahdab N, Alharbi Majed, Darwish Khaled M, Elhady Sameh S, Khafagy El-Sayed, Safo Martin K, Hegazy Wael A H
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
Biomedicines. 2022 May 18;10(5):1169. doi: 10.3390/biomedicines10051169.
The development of bacterial resistance to traditional antibiotics constitutes an emerging public health issue. Promising approaches have been innovated to conquer bacterial resistance, and targeting bacterial virulence is one of these approaches. Bacterial virulence mitigation offers several merits, as antivirulence agents do not affect the growth of bacteria and hence do not induce bacteria to develop resistance. In this direction, numerous drugs have been repurposed as antivirulence agents prior to their clinical use alone or in combination with traditional antibiotics. Quorum sensing (QS) plays a key role in controlling bacterial virulence. In the current study, dipeptidase inhibitor-4 (DPI-4) antidiabetic gliptins were screened for their antivirulence and anti-quorum sensing (anti-QS) activities against Gram-negative and Gram-positive . Upon assessing their antibiofilm activities, the ten tested gliptins significantly diminished biofilm formation. In particular, sitagliptin exhibited the most efficient antibiofilm activity, so it was chosen as a representative of all gliptins to further investigate its antivirulence activity. Sitagliptin significantly protected mice from and pathogenesis. Furthermore, sitagliptin downregulated QS-encoding genes in and . To test the anti-QS activities of gliptins, a detailed molecular docking study was conducted to evaluate the gliptins' binding affinities to and QS receptors, which helped explain the anti-QS activities of gliptins, particularly sitagliptin and omarigliptin. In conclusion, this study evaluates the possible antivirulence and anti-QS activities of gliptins that could be promising novel candidates for the treatment of aggressive Gram-negative or -positive bacterial infections either alone or as adjuvants to other antibiotics.
细菌对传统抗生素产生耐药性已成为一个新出现的公共卫生问题。人们创新了一些有前景的方法来克服细菌耐药性，靶向细菌毒力就是其中之一。减轻细菌毒力有诸多优点，因为抗毒力药物不会影响细菌生长，因此不会诱导细菌产生耐药性。在这一方向上，许多药物在单独或与传统抗生素联合临床使用之前，已被重新用作抗毒力药物。群体感应（QS）在控制细菌毒力方面起关键作用。在本研究中，对二肽基肽酶抑制剂 -4（DPI -4）类抗糖尿病格列汀类药物针对革兰氏阴性菌和革兰氏阳性菌的抗毒力和抗群体感应（抗QS）活性进行了筛选。在评估它们的抗生物膜活性时，所测试的10种格列汀类药物显著减少了生物膜形成。特别是，西他列汀表现出最有效的抗生物膜活性，因此被选为所有格列汀类药物的代表，以进一步研究其抗毒力活性。西他列汀显著保护小鼠免受[具体细菌名称1]和[具体细菌名称2]致病作用的影响。此外，西他列汀下调了[具体细菌名称1]和[具体细菌名称2]中群体感应编码基因。为了测试格列汀类药物的抗QS活性，进行了详细的分子对接研究，以评估格列汀类药物与[具体细菌名称1]和[具体细菌名称2]的QS受体的结合亲和力，这有助于解释格列汀类药物，特别是西他列汀和奥格列汀的抗QS活性。总之，本研究评估了格列汀类药物可能的抗毒力和抗QS活性，它们可能是单独治疗侵袭性革兰氏阴性或阳性细菌感染或作为其他抗生素佐剂的有前景的新型候选药物。
