Frontiers in Anti-Infective Drug Discovery

Volume: 2

Development of Synthetic Antimicrobial Peptides as Therapeutic Agents to Treat Drug Resistant Bacterial and Fungal Infections

Author(s): Rickey P. Hicks and Tiffany D. Clark

Pp: 86-158 (73)

DOI: 10.2174/9781608058600114020004

* (Excluding Mailing and Handling)

Abstract

The continued evolution of multiple drug resistant organisms associated with common bacterial and fungal infections have become a critical and life threatening challenge facing modern medicine. To overcome this challenge new therapeutic agents that kill these organisms via novel mechanisms of action must be developed. Antimicrobial peptides offer several advantages as potential therapeutic agents against multiple drug resistant organisms. Their greatest advantage is their unique mechanism of action which involves first the disruption of the target’s cell membrane followed by lysis of the cell thus causing cell death. However, natural antimicrobial peptides also have several inherent disadvantages these included low metabolic stability, lack of bacterial strain selectivity and toxicity toward human cells. In this chapter the development of synthetic antimicrobial peptides containing both natural and unnatural amino acids as well as peptidomimetics designed to address these disadvantages will be discussed. An overview of the physicochemical properties required for antimicrobial activity will be presented with emphasis on the logic of the process of designing new antimicrobial peptides. Specific examples of synthetic antimicrobial peptides will be presented to highlight the application of various approaches to address the issues of metabolic stability, increasing the selectivity for prokaryotic verses eukaryotic cells, as well as increasing bacterial strain selectivity and potency. In addition the chemical analysis methods of Circular Dichroism spectroscopy (CD), isothermal calorimetry (ITC) and fluorescence spectroscopy to monitor calcein induced leakage from liposomes will be discussed. These techniques provide physicochemical information concerning peptide-lipid interactions which provide critical insight for the design of therapeutically useful antimicrobial peptides.


Keywords: Antimicrobial peptides, unnatural amino acids, peptide-lipid interactions, peptidomimetics, β-peptides, organism selectivity, circular dichroism spectroscopy, isothermal calorimetry, mechanism of antibacterial activity.

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      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1518
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59884719 and j.to_ip >=59884719 )) and ((j.from_date <= 1740345738 and j.to_date >= 1740345738 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6121) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59884719 and j.to_ip >=59884719 )) and ((j.from_date <= 1740345738 and j.to_date >= 1740345738 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6121) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59884719 and j.to_ip >=59884719 )) and ((j.from_date <= 1740345738 and j.to_date >= 1740345738 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6121)
      560μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 1474 and `b`.`banner_from_date` <= 1740345738 and `b`.`banner_to_date` >= 1740345738 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.06msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 1474
      • 3: 1740345738
      • 4: 1740345738
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='688ef489a58e3e3f958a1017d45ccc42'
      240μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    9Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        A1aRRLkH2aSpqce4SQcTzezLBGWZWPgZ63JGTzLr
        uc_cart_id
        688ef489a58e3e3f958a1017d45ccc42
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/6121" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/6121
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:17 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6IitYNGNoWDRwTUdCdllVQkM1N2tVQmc9PSIsInZhbHVlIjoiMFlBQVM4M2hhTEdHd3F3UXVxeVM2MVA1dzZDVFRYVFQwN2JnU2tubE9Xbz0iLCJtYWMiOiIxMDQ5M2RhOWZhZGM5ZWJlYTZkN2I3Yjc2NDU5Y2U4NzU0Zjg5MDM4NWVjMTg5NzQwZmNhYmJmYzU0YWZlN2I5IiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6IitYNGNoWDRwTUdCdllVQkM1N2tVQmc9PSIsInZhbHVlIjoiMFlBQVM4M2hhTEdHd3F3UXVxeVM2MVA1dzZDVFRYVFQwN2JnU2tubE9Xbz0iLCJtYWMiOiIxMDQ5M2RhOWZhZGM5" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Sun, 23 Feb 2025 21:22:18 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IjJHVEE3S2NvZ2hJbEtOZHVLMjhlaGc9PSIsInZhbHVlIjoidWowdmJmUnA1SkIxRkVZQ0cxeXZZUlo4dFhzaHAzNHFtbnFQbmpkeHN2ZHFHcnFSWTFpSFNFWHRnWVc2b1A0TE1MMlJucUdmZzNwWDFaMFdTanU5dGdob0xLdlpTY2Z3Z1JVWFZCWXpZUU94UHkwUkNnNmFXdExGcU9yMEVrRE8iLCJtYWMiOiI0N2JhMjQ4NGMwYzZmOTI0ZjU4YzE3MmJjODYwNDc1ZGM2MmNkNmQ5Mjg4YmYwYmQ5YzgxM2RjNDU5NzFmZDdlIiwidGFnIjoiIn0%3D; expires=Wed, 26 Feb 2025 09:22:18 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IjJHVEE3S2NvZ2hJbEtOZHVLMjhlaGc9PSIsInZhbHVlIjoidWowdmJmUnA1SkIxRkVZQ0cxeXZZUlo4dFhzaHAzNHFtbnFQbmpkeHN2ZHFHcnFSWTFpSFNFWHRnWVc2b1A0TE1MMlJuc" 1 => "alphaeurekaselectnet_session=eyJpdiI6IklsWG5aaHgzTkN1VTJuc3V4bDMxRHc9PSIsInZhbHVlIjoiWlFDKytoQzRsZVdHWWw5SmI4MWNiZy9qOGMrLzEwL2FidStyV2kxZ2szQnlOQys5N2hmcUpFQ0VkR0s0aFN4M3BSSmt5enIydFhXbjRiTjdaZmFnMzl6cGJxWFkxY0hkVTlhUjdNWXdWMFVQY3k5Y3BIRS9RQnV1cXRMOFJSRk4iLCJtYWMiOiI1YjMwZjRhNzg3NmNmY2U5ZWQ1YjJmZjM5YzdkYjQ3MWNjYjQ1N2FiMzU2MTljMGQzYzM3NDc3YmU1NTNlZTk5IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IklsWG5aaHgzTkN1VTJuc3V4bDMxRHc9PSIsInZhbHVlIjoiWlFDKytoQzRsZVdHWWw5SmI4MWNiZy9qOGMrLzEwL2FidStyV2kxZ2szQnlOQys5N2hmcUpFQ0V" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IjJHVEE3S2NvZ2hJbEtOZHVLMjhlaGc9PSIsInZhbHVlIjoidWowdmJmUnA1SkIxRkVZQ0cxeXZZUlo4dFhzaHAzNHFtbnFQbmpkeHN2ZHFHcnFSWTFpSFNFWHRnWVc2b1A0TE1MMlJucUdmZzNwWDFaMFdTanU5dGdob0xLdlpTY2Z3Z1JVWFZCWXpZUU94UHkwUkNnNmFXdExGcU9yMEVrRE8iLCJtYWMiOiI0N2JhMjQ4NGMwYzZmOTI0ZjU4YzE3MmJjODYwNDc1ZGM2MmNkNmQ5Mjg4YmYwYmQ5YzgxM2RjNDU5NzFmZDdlIiwidGFnIjoiIn0%3D; expires=Wed, 26-Feb-2025 09:22:18 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IjJHVEE3S2NvZ2hJbEtOZHVLMjhlaGc9PSIsInZhbHVlIjoidWowdmJmUnA1SkIxRkVZQ0cxeXZZUlo4dFhzaHAzNHFtbnFQbmpkeHN2ZHFHcnFSWTFpSFNFWHRnWVc2b1A0TE1MMlJuc" 1 => "alphaeurekaselectnet_session=eyJpdiI6IklsWG5aaHgzTkN1VTJuc3V4bDMxRHc9PSIsInZhbHVlIjoiWlFDKytoQzRsZVdHWWw5SmI4MWNiZy9qOGMrLzEwL2FidStyV2kxZ2szQnlOQys5N2hmcUpFQ0VkR0s0aFN4M3BSSmt5enIydFhXbjRiTjdaZmFnMzl6cGJxWFkxY0hkVTlhUjdNWXdWMFVQY3k5Y3BIRS9RQnV1cXRMOFJSRk4iLCJtYWMiOiI1YjMwZjRhNzg3NmNmY2U5ZWQ1YjJmZjM5YzdkYjQ3MWNjYjQ1N2FiMzU2MTljMGQzYzM3NDc3YmU1NTNlZTk5IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IklsWG5aaHgzTkN1VTJuc3V4bDMxRHc9PSIsInZhbHVlIjoiWlFDKytoQzRsZVdHWWw5SmI4MWNiZy9qOGMrLzEwL2FidStyV2kxZ2szQnlOQys5N2hmcUpFQ0V" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "A1aRRLkH2aSpqce4SQcTzezLBGWZWPgZ63JGTzLr" "uc_cart_id" => "688ef489a58e3e3f958a1017d45ccc42" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/6121" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-23 21:22:18GET/chapter/61211121911