aminoglycoside bactericidal mechanism.docx

2
Aminoglycosides display concentration-dependent bactericidal activity against "most gram-negative aerobic and facultative anaerobic bacilli" apart from some bacilli and methicillin-resistant staphylococci, but not against gram-negative anaerobes and most gram-positive bacteria. [3]  They require only short contact time, and are most effective against susceptible bacterial populations that are rapidly multiplying. [8]  These activities are attributed to a primary mode of action as  protein synthesis inhibitors, though additional mechanisms are implicated for some specific agents, and/or thorough mechanistic descriptions are as yet unavailable. [2][3][8]  The inhibition of protein synthesis is mediated through aminoglycosides' energy-dependent, sometimes irreversible binding, to the  cytosolic, membrane- associated bacterial  ribosome (image at right, mouse-over for legend). [2]  (Aminoglycosides first cross bacterial cell walls   lipopolysaccharide in gram-negative bacteria)   and cell membranes, where they are actively transported. [8] ) While specific steps in protein synthesis affected may vary somewhat between specific aminoglycoside agents, as can their affinity and degree of binding, [8]  aminoglycoside presence in the cytosol generally perturbs  peptide elongation at the 30S ribosomal subunit, giving rise to inaccurate mRNA translation and so biosynthesis of proteins that are truncated or that bear altered amino acid compositions at particular points. [2]  Specifically, binding impairs translational proofreading leading to misreading of the RNA message,  premature termination, or both, and so to inaccuracy of the translated  protein  product. The subset of aberrant proteins that are incorporated into the bacterial cell membrane may then lead to changes in its permeability and then to "further stimulation of aminoglycoside transport". [2]  The amino-sugar portion of this class of molecules (e.g., the 2-deoxystreptamine in kanamycins, gentamicins, and tobramycin, see above) are implicated in the association of the small molecule with ribosomal structures that lead to the infidelities in translation (ibid.). Inhibition of  ribosomal translocation   i.e., movement of the peptidyl-tRNA from the A- to the P-site   has also been suggested. [citation needed ]  (Spectinomycin, a related but distinct chemical structure class often discussed with aminoglycosides, does not induce mRNA misreading and is generally not bactericidal. ) [8]  Finally, a further "cell-membrane effect" also occurs with aminoglycosides; "functional integrity of the bacterial cell membrane" can be lost, later in time courses of a minoglycoside exposure and transport . [9]  

Upload: tazyinul-qoriah-alfauziah

Post on 09-Oct-2015

5 views

Category:

Documents


0 download

TRANSCRIPT

Aminoglycosides display concentration-dependent bactericidal activity against "most gram-negative aerobic and facultative anaerobic bacilli" apart from some bacilli and methicillin-resistant staphylococci, but not against gram-negative anaerobes and most gram-positive bacteria.[3]They require only short contact time, and are most effective against susceptible bacterial populations that are rapidly multiplying.[8]These activities are attributed to a primary mode of action asprotein synthesis inhibitors, though additional mechanisms are implicated for some specific agents, and/or thorough mechanistic descriptions are as yet unavailable.[2][3][8]The inhibition of protein synthesis is mediated through aminoglycosides' energy-dependent, sometimes irreversible binding, to thecytosolic, membrane-associated bacterialribosome(image at right, mouse-over for legend).[2](Aminoglycosides first cross bacterial cell wallslipopolysaccharidein gram-negative bacteria)and cell membranes, where they areactively transported.[8]) While specific steps in protein synthesis affected may vary somewhat between specific aminoglycoside agents, as can their affinity and degree of binding,[8]aminoglycoside presence in the cytosol generally perturbs peptide elongation at the30Sribosomalsubunit, giving rise to inaccurate mRNA translation and so biosynthesis of proteins that are truncated or that bear altered amino acid compositions at particular points.[2]Specifically, binding impairstranslational proofreadingleading to misreading of the RNA message, premature termination, or both, and so to inaccuracy of thetranslatedprotein product. The subset of aberrant proteins that are incorporated into the bacterial cell membrane may then lead to changes in its permeability and then to "further stimulation of aminoglycoside transport".[2]The amino-sugar portion of this class of molecules (e.g., the 2-deoxystreptamine in kanamycins, gentamicins, and tobramycin, see above) are implicated in the association of the small molecule with ribosomal structures that lead to the infidelities in translation (ibid.). Inhibition ofribosomal translocationi.e., movement of the peptidyl-tRNA from the A- to the P-sitehas also been suggested.[citation needed](Spectinomycin, a related but distinct chemical structure class often discussed with aminoglycosides, does not induce mRNA misreading and is generally not bactericidal.)[8]Finally, a further "cell-membrane effect" also occurs with aminoglycosides; "functional integrity of the bacterial cell membrane" can be lost, later in time courses of aminoglycoside exposure and transport.[9]

Nama: Tazyinul Qoriah AlfauziahNPM: 260110120027Tugas Farmakologi KemoterapiMekanisme Sifat Bakterisidal AminoglikosidaAminoglikosida display konsentrasi tergantung aktivitas bakterisidal terhadap "sebagian gram negatif aerobik dan fakultatif anaerob basil" terlepas dari beberapa basil dan methicillin-resistant staphylococcus, tapi tidak melawan anaerob gram negatif dan sebagian besar bakteri gram positif [3] Mereka hanya memerlukan singkat. hubungi waktu, dan yang paling efektif terhadap populasi bakteri rentan yang cepat berkembang biak. [8] kegiatan ini dikaitkan dengan modus utama tindakan sebagai sintesis protein inhibitor, meskipun mekanisme tambahan yang terlibat untuk beberapa agen tertentu, dan / atau deskripsi mekanistik menyeluruh adalah sebagai belum tersedia. [2] [3] [8] Penghambatan sintesis protein dimediasi melalui aminoglikosida 'energi tergantung, kadang-kadang ireversibel mengikat, ke sitosol, membran-terkait ribosom bakteri (gambar di sebelah kanan, mouse-over untuk legenda) [2] (Aminoglikosida pertama sel bakteri lintas. Dinding-lipopolisakarida pada bakteri gram negatif) -dan sel membran, di mana mereka secara aktif diangkut. [8]) Sementara langkah-langkah spesifik dalam sintesis protein yang terkena mungkin agak berbeda antara agen aminoglikosida spesifik, seperti dapat afinitas mereka dan tingkat mengikat, [8] aminoglikosida kehadiran di sitosol umumnya perturbs peptida elongasi pada 30S ribosomal subunit, sehingga menimbulkan terjemahan mRNA akurat dan biosintesis protein yang dipotong atau beruang diubah amino komposisi asam pada titik-titik tertentu. [2] secara khusus, mengikat mengalami korosi akibat gesekan translasi proofreading mengarah ke salah membaca pesan RNA, penghentian prematur, atau keduanya, dan sehingga untuk ketidaktelitian produk protein diterjemahkan. Subset protein menyimpang yang dimasukkan ke dalam membran sel bakteri kemudian dapat menyebabkan perubahan permeabilitas dan kemudian ke "rangsangan lebih lanjut dari transportasi aminoglikosida". [2] Bagian amino-gula kelas ini molekul (misalnya, 2 -deoxystreptamine di kanamycins, gentamicins, dan tobramycin, lihat di atas) yang terlibat dalam asosiasi molekul kecil dengan struktur ribosom yang mengarah ke perselingkuhan dalam terjemahan (ibid.). Penghambatan ribosom translokasi-yaitu, gerakan peptidil-tRNA dari A- ke P-site-juga telah disarankan. [Rujukan?] (Spectinomycin, yang terkait tetapi berbeda kimia struktur kelas sering dibahas dengan aminoglikosida, tidak menyebabkan mRNA salah membaca dan umumnya tidak bakterisida.) [8] Akhirnya, lanjut "efek-membran sel" juga terjadi dengan aminoglikosida; "integritas fungsional dari membran sel bakteri" bisa hilang, kemudian dalam program saat paparan aminoglikosida dan transportasi. [9]