抗生素,抗生素耐药性与环境

antibiorésistance - antibiotiques - antibiotics - antibiotics resistance

  微生物自身会产生抗生素,抑制其他竞争性微生物的生长。为了生存,微生物通过遗传和生化机制进化出了抗生素抗性, 并通过频繁的遗传物质互换在种群间广泛传播。然而,自1940年代以来,人类开发出了新型抗生素,使用量逐年增大 。在15年间,全球抗生素消费量增长了65%,主要集中于中低收入国家。目前,全球性的抗生素大规模使用已成为一个主要的公众健康隐患。 某些对人和动物具有致病性的细菌已经对制药工业开发的大多数抗生素分子产生了耐药性。除此之外,施用于人和动物的抗生素,以及来源于宿主的耐药菌已在环境中广泛传播。 细菌正向抗生素耐药性能力增加的方向进化。 环境、动物或人类宿主中的菌群之间的基因交换永远存在。 因此,对抗生素耐药性的斗争必需全面考虑。抗生素对不同宿主的影响难道不应该被考虑在内吗?

1. 细菌耐药性:一个全球性的健康威胁

环境百科全书-抗生素-生素靶点和细菌耐药机制
图1. 抗生素靶点和细菌耐药机制。这张图展示了抗生素的主要作用靶点和细菌对抗生素耐药的主要机制。列出了每种情况下相关的抗生素家族。
[来源: Creative Commons Attribution 2.0 Generic License.]
抗生素靶点 抗生素耐药性机制
细胞壁:β-内酰胺类 万古霉素类 流出:氟喹诺酮类 氨基糖甙类 四环素类
β-内酰胺类 大环内酯类
DNA/RNA合成:氟喹诺酮类 利福霉素类
叶酸合成:甲氧苄氨嘧啶类 磺胺类 不渗透性:四环素类 甲氧苄氨嘧啶类 磺胺类万古霉素类
细胞膜:达托霉素类 靶点修饰:氟喹诺酮类 利福霉素类 万古霉素类 青霉素类 大环内酯类 氨基糖甙类
蛋白质合成:利奈唑胺类 四环素类 大环内酯类 氨基糖甙类 灭活酶:β-内酰胺类 氨基糖甙类 大环内酯类 利福霉素类

  一组抗生素耐药性对公众健康风险影响的数据值得研究人员警惕:2015年,全球每天消耗423亿剂的抗生素 。耐药性指某些细菌耐受一种或多种抗生素作用的能力,由细菌基因组中的某些基因编码。 对于特定抗生素,细菌的耐受性主要包括四种生物化学机制:

  • 细菌膜对该抗生素的抗渗性;
  • 细菌对渗入抗生素的外排;
  • 通过对作用靶点的定量或定性修饰,降低抗生素与细菌靶点的亲和力;
  • 利用细菌酶使抗生素失活。
环境百科全书-抗生素-接合和转导
图2. 接合和转导。结合(左)。1. 供体细菌具有受体细菌所没有的接合质粒。2. 供体细菌通过菌毛与受体细菌建立接触。3.供体细菌复制其质粒并将其转移到受体细菌。4. 受体细菌获得了新的质粒基因,同时自身也成为供体细菌。转导(右)。1. 病毒(噬菌体)感染细菌。2. 病毒基因组合并到细菌基因组和病毒复制。3.包含细菌基因组片段的病毒包衣。4. 被这种噬菌体感染的新细菌。5. 病毒将细菌基因组片段从供体细菌传播到受体细菌。6. 受体细菌整合了供体细菌片段,从而赋予它新的特性(毒性、抗生素耐药性等)。
[来源: 左侧翻译自By derivative work: Franciscosp2 (talk) Bacterial_Conjugation_en.png: Mike Jones (Bacterial_Conjugation_en.png) [CC BY-SA 2.5], via Wikimedia Commons ; 右侧翻译自By Reytan with modifications by Geni & Toony (common Image: Transduction (genetics)en.svg) [Public domain], via Wikimedia Commons.]
接合:1.质粒 菌毛 细菌 染色体2.供体细菌 受体细菌3.松弛体 转染体4.新的供体 旧的供体 转导:1噬菌体 细菌5.病毒DNA 细菌DNA 6.重组基因组的细菌

  图1概述了抗生素的作用靶点和细菌对这些分子的耐药性机制。

  某些种类细菌的耐药性机制稳定,并影响大多数菌株:我们称之为天然耐药性。相反,当某类对抗生素敏感细菌的特定菌株通过遗传机制获得抗性时,即会产生获得性耐药性 。获得新的抗生素耐药性可能与突变相关,并受抗性基因的特性和表达水平影响(参见Genetic Polymorphism and Variation)。也可能是获得新的耐药基因的结果。事实上,移动基因元件[1](质粒、转座子、整合子等)可以在相同或不同种类的细菌之间交换。这些交换通过水平基因转移机制[2](接合、转化、转导、转座)进行(图2和3)。所有存在于致病性或非致病性微生物中的抗生素耐药性基因构成了抗性组。

环境百科全书-抗生素-转化和转座
图3. 转化和转座。转化(左)。Ⅰ. 细菌A在它的环境中释放一个基因(细菌的活性机制或裂解机制)。Ⅱ. 细菌B捕获这个外源基因并将其整合到细胞质中。Ⅲ. 细菌B将这个基因整合到它的基因组中(本例中是质粒基因 )。Ⅳ. 细菌B具有编码例如抗生素耐药性的新基因。转座(右)。1. 供体DNA包含由两个插入序列(IS)包围的一个转座子。该转座子可能包含编码为不同功能(毒力 、抗生素耐药性等)的多个基因。2. 转座酶与 。3. 形成转座复合体 。4. 转座子被切除。5. 将此转座子移动到DNA目标位点,在同一复制子上(染色体或质粒),或另一个复制子上(例如从染色体转移到质粒上)。6. 转座子插入目标DNA,赋予其新的特性。
[来源:左边改编自By Sprovenzano15 [CC BY-SA 3.0], from Wikimedia Commons; 右边改编自 Alana Gyemi [CC BY-SA 4.0], from Wikimedia Commons.]
转化:细菌A,细菌B 1.chromosome染色体;2.transferred gene(G)转移的基因(G);3.restriction enzyme限制性内切酶;4.DNA ligase DNA连接酶;5.bacteriumA plasmid carrying the gene G 携带基因G的细菌A质粒6.bacteriumB plasmid integrating the gene G整合基因G的细菌B质粒
转座:insertion sequence插入序列; donor DNA供体DNA;transposon转座子; transposase转座酶; transposase fixation转座酶固定; transposition complex formation转座复合物的形成; excision切除; recognition of the target DNA site识别靶DNA位点; target DNA靶DNA; transposon insertion in the target DNA site转座子插入靶DNA位点.

  在过去的80年里,抗生素的大量使用导致了新的抗生素耐药性机制的选择和种间转移。在同一种细菌中的耐药性的累积导致多耐药性(对多个抗生素家族产生耐药性,MDR),甚至是完全耐药性(对所有可用抗生素产生耐药性)。这两种情况会造成治疗僵局。某些经常涉及人体病理,且对多种抗生素具有耐药性的细菌种类被统称为超级耐药菌(ESKAPE)[3],包含屎肠球菌、金黄色葡萄球菌、肺炎克雷伯菌、鲍曼不动杆菌、铜绿假单胞菌、肠杆菌及最近发现的其他肠杆菌科细菌(非大肠杆菌)(表1)。

  当前,细菌耐药性是一个重大的全球公共卫生问题, 需要依靠国际(包括世卫组织)和国家控制计划的进程。尽管已在人和动物宿主中鉴定了抗生素耐药性,但直到最近才认识到环境在耐药性的出现和传播中起到的作用。

2. 环境:古老的抗生素耐药性宿主

  许多环境微生物 (尤其是细菌和真菌)可以自发地产生抗生素,因此赋予它们较其他环境物种具有选择性生长的优势。这些微生物具有抵抗自产抗生素的耐药性机制的基因编码。它们可以把这些耐药性基因传递给后代(垂直传递)[4]。不产生抗生素的微生物也可能携带抗生素抗性基因或从头获得它们。在细菌中,相同或不同物种的个体之间存在许多遗传交换(水平传递)。 生活在环境中细菌之间的耐药性传播可能从很久以前(几十亿年)就开始了,并持续至今[5]这些耐药性可以从环境细菌传播到人类和动物身上的细菌。例如,最近出现的CTX-M型广谱b-内酰胺酶(ESBLs)或对氟喹诺酮类药物(qnr基因)产生耐药性的新机制[6]

3. 人造抗生素的环境释放

  20世纪初的重大标志是发现并大量生产天然抗生素(从微生物中提取)或通过化学合成获得。天然抗生素包括b-内酰胺类抗生素(包括青霉素)、氨基糖苷类、四环素类和大环内酯类药物。其中大部分天然分子经过化学修饰,成为半合成抗生素或最近的合成抗生素。磺胺类和喹诺酮类药物是人类直接合成的分子。从20世纪40年代到现在,人和动物使用的抗生素呈指数式增长,相当于向环境释放了数百万吨的抗生素。抗生素对环境的污染主要有三种来源:

  • 抗生素工业生产厂向水环境的排放;
  • 饲养家畜所使用的抗生素;
  • 用过抗生素的人。

3.1. 抗生素生产工厂

  抗生素生产工厂通过废水排放了大量的抗生素。 在大量生产抗生素的国家,特别是在欧洲、美国、中国和印度,目前在环境污染方面的监管限制是不够的。某些工厂的废水中可检测到的抗生素浓度超过1毫克/升[7]。这种浓度对环境微生物菌群有显著影响。此外,环境中抗生素的广泛传播会污染地下水。

3.2. 兽医使用的抗生素

  家畜的抗生素施用(很少包含野生动物)约占抗生素总产量的约60% ,并且还在持续增加[8]。全世界每年施用于家畜、低地动物和水产养殖的抗生素超过10万吨[9]。最常用的是四环素,其次是青霉素类和磺胺类药物。然而,b-内酰胺类抗生素、氨基糖苷类、氯霉素类、大环内酯类和糖肽类药物也同样受到关注 。人和动物所使用的抗生素属于相同的家族,因此也会由于相同的 耐药性机制而失活。抗生素用于治疗和预防家畜的传染病(抗生素预防),或者作为食物补充剂。为了治疗和预防细菌感染,即使只有少量家禽患病,抗生素常被添加到饮用水或整个农场的饲料中 。系统地使用抗生素作为饲料补充剂 (尤其是家畜、家禽、鱼等)是为了提高牲畜的产量 (例如,就生产肉的量而言 )。

  数十年来,这种以盈利为目的使用抗生素的做法一直占绝大多数 。目前这种做法在欧洲已被禁止, 但在许多国家仍然存在。这被认为是动物消化道内定植细菌(如大肠杆菌)产生耐药性的主要原因。大多数从这些动物中筛选出来的耐药菌可以通过接触或被污染的食品传播给人类。 此外,动物服用的抗生素也在其粪便中保有活性。这些农场的废水 通常直接排放到水环境中,或未经事先处理就用于作物灌溉。

3.3. 人类对抗生素的使用

  人类使用抗生素治疗或预防传染病(抗生素预防)。全球人口每年消耗数百亿单位剂量的抗生素。b-内酰胺类抗生素(青霉素类、头孢菌素类、碳青霉烯类)是目前使用最广泛的抗生素(约占人类消耗量的60%)。四环素类、大环内酯类和氟喹诺酮类药物的用量也很大。大约80%的抗生素在社区中使用,20%在医院使用。然而,由于广谱抗生素的使用和选择性耐药菌人传人的高风险 [10],因此医疗保健机构在细菌耐药性传播方面的角色很重要。一些开给患者的抗生素处方药没有被使用,因此和我们的日常废物一起释放到环境中。

  更为重要的是,人体吸收的大部分抗生素通过尿液和粪便排出时仍具有活性。在发展中国家,这些抗生素被直接分散在大地-水环境中 。在拥有废水处理基础设施的国家,大部分的抗生素会被废水处理厂截留[11]。在一些处理厂的废水中可检测到的抗生素(b-内酰胺类、大环内酯类、四环素类、氟喹诺酮类等)浓度大约为mg/L级。这些抗生素被生物降解,被污水污泥吸附,或通过工厂废液排出。污泥可用作农田肥料,而污水被排入水环境(河流)。这两种情况下,活性抗生素将被释放到水陆环境中

  • 环境中的抗生素残留浓度

  在一些水和陆地环境中,可检测到的抗生素浓度介于纳克至微克每升水或每克土壤。一些地下水中也可测到类似的浓度。在污染后,这些抗生素会在环境中持续存在一段时间,从几天(如b-内酰胺抗生素)至几个月(如氟喹诺酮类和四环素类药物)。对于后者,如果环境污染频繁或持久,就会出现抗生素的累积现象。海洋环境中也可以检测到抗生素的残留。最终,有时在饮用水中可以检测到浓度在纳克每升水平的抗生素残留。

4. 人源和动物源的新型抗生素抗性基因的环境释放

  用于人和动物的抗生素是筛选其共生菌群(其微生物菌群)中抗生素抗性最强的细菌种类和菌株。(参见Human microbiots: Allies for our health)。

  通过促进基因突变和抗生素抗性的水平基因转移,抗生素还会在细菌SOS系统中诱导耐药性。这种现象在菌群丰富、细菌种类多达几千种的肠道菌群中尤为重要(图4)。

环境百科全书-抗生素-消化道的微生物群
图4.消化道的菌群。口腔、口咽、回肠末端和结肠的微生物群丰富多样。由于胃部的强酸性环境,这里的微生物群相对较少。厌氧细菌(在无氧情况下繁殖)在结肠中广泛存在。
[来源: Adapted from By Mariana Ruiz, Jmarchn, Translated in French by Moez [Publicdomain], from Wikimedia Commons.]
Number of bacteria细菌数量; major bacterial phyla主要细菌门; mouth and oropharynx口腔和口咽; stomach胃; duodenum十二指肠; colon结肠; jejunum and ileum空肠和回肠;
Firmicutes厚壁菌门:梭菌,肠球菌,葡萄球菌群,链球菌,乳杆菌…
Bacteroidetes拟杆菌门:细菌,卟啉单胞菌…
Actinobacteria放线菌门:棒状杆菌,丙酸杆菌,双歧杆菌…
Proteobacteria变形细菌门:大肠埃希氏菌,假单胞菌,奈瑟菌…

  人和动物向环境中传播构成其共生菌群的细菌,特别是携带抗生素抗性基因的细菌。有些种类的细菌可以在环境(水、土壤、被污染的物品等)中存活很长时间。由于人类活动,废水处理厂汇聚了大量废水 ,聚集了大量抗生素耐药菌及其抗性基因。严重污染的污泥常被用作农地化肥。净化后仍不达标的水被释放到环境中, 然而这些水仍然含有细菌和抗生素抗性基因。因此,污水处理厂是新的抗生素抗性基因造成环境污染的主要源头。

5. 环境中出现的新的抗生素抗性产物

  水陆环境介质富含微生物,其多样性仅得到部分表征。近期宏基因组学研究导致许多新菌种的发现 。研究表明,超过99%的环境细菌物种不能用目前的方法培养[12]

  环境持续被人源或动物源抗生素抗性细菌、抗性基因编码以及人类制造的抗生素污染。 植物会吸收部分抗生素,尤其是被来自于废水处理厂含抗生素的污水或污泥灌溉的农作物。虽然环境中残留的抗生素浓度通常很低,但它们对天然微生物菌群的筛选压力日益增加。这种筛选压力促进了天然物种和污染物种之间抗生素抗性基因的水平交换,特别是对于在生物膜中丰富多样的细菌种群。这些微生物的天敌,即自由生存的原生动物(特别是变形虫),也促进了这些基因的交换。

  总而言之,无论是在自然环境中的细菌菌群中,还是能够在这种环境中生存的人类和动物菌群中。 环境中已经具备新的抗生素抗性出现的条件。

6. 环境是人类和动物中新抗生素抗性的来源

  来自水陆环境的微生物经常定植在人类和动物身上。这种定植可直接通过日常活动与环境接触而发生,或间接通过饮食、饮水,亦或被污染的物品而发生[13]。与人和动物共生的微生物菌群作为微生物屏障,可防御被一些机体缺乏适应性的外来物种感染。尽管如此,许多源自人类和动物的细菌物种仍可在环境中生存 ,并且能再次感染宿主。另一方面,环境微生物可以在人和动物的皮肤和粘膜中定植。这种定植可能是瞬时的、短期的(几小时或几天),或长期的(几周、几个月甚至几年)。在定殖期间,外源菌群和内源共生菌群之间的遗传交换会不断发生。由于消化道菌群的丰富性和多样性,并且许多环境微生物被摄入后在肠道内长时间停留,因此这些消化菌群的遗传交换尤为重要。

  需要注意的是,耐药菌对抗菌剂同样会产生抗性,包括重金属(银、铜、汞等)和生物杀菌剂(乙醇、甲醛、洗必泰、三氯生、季铵盐 等。抗菌剂的环境污染会促使耐药菌的形成。两种现象可能有助于理解抗菌剂对耐药性菌株的筛选(或为抗菌剂抗性的抗生素选择):

  • 抗生素和抗菌剂的抗性遗传机制由相同的基因载体(特别是质粒)携带;细菌暴露于抗生素或抗菌剂会筛选对这两类化合物都具有抗性的菌株,即为复合抗性;
  • 相同的遗传机制(例如外排泵的基因编码)导致细菌对抗生素和抗菌剂同时产生抗性; 当这些分子中的一种或另一种存在时,会引起两类抗性的筛选,即为交叉抗性。

7. 综合展望:更好地理解与环境和集约化畜牧业相关的风险

环境百科全书-抗生素-抗生素、耐药细菌及其耐药基因对环境的污染
图5. 抗生素、耐药菌及其抗性基因对环境的污染。人类和动物(家畜、家禽、养殖鱼类等)的共生菌群和病原性菌群遭受到来自社区、护理机构和家畜养殖中抗生素选择的压力。 因抗生素抗性而筛选的细菌会直接或通过污水处理厂排放到自然环境中。这些耐药菌在人类和动物之间传播(直接接触、食物等)。环境本身就是细菌产生新的抗生素抗性的来源,这些细菌可以污染 人类和动物。
Cattle, fish farming, farmers, health-care facilities, pharmaceutical production plant, community, waste water treatment plant, environment, food, abattoir workers, poultry
牛,养鱼,农民,卫生保健机构,制药厂,社区,废水处理厂,环境,食品,屠宰场工人,家禽

  抗菌药物耐药性是一个复杂且长期存在的现象,已成为人类和动物健康的一个主要问题,由三个因素共同作用 :1/几十年间抗生素的过度使用;2/基因组的高可塑性,并因此使得细菌能够适应选择压力; 3/环境、动物和人类:三个主要抗性基因库之间永远存在交换(图5) 。

  大量而迅速的国际贸易 (人类、动物、食品)使这种情况恶化。环境受到来自于人源和动物源的耐药微生物以及残留抗生素的污染。这两类污染促进了新的抗生素抗性的出现以及细菌物种之间的耐药性转移。

  由于人、动物和环境三者之间存在很强的相互作用,因而抗菌药物耐药性遗传机制的扩散广泛迅猛。与其他环境污染物(其他药物、化学品、重金属等)相比,这种污染具有能在人类和动物群体中潜在传播的特征。事实上,耐抗生素细菌在人与人、动物与动物和人与动物之间的传播不仅解释了这种污染的个体效应,也解释了其群体效应。在防治抗菌药物耐药性出现和传播的方法中,以下几点至关重要:

  • 减少和优化抗生素的使用量;
  • 避免或至少限制抗生素和携带抗性基因的细菌在环境中的传播,特别是重要的源头(医院、抗生素制造厂、集约型畜牧场、污水处理厂等);
  • 提高发展中国家的卫生水平并开发水净化系统;
  • 更好地监测抗生素及其抗生素抗性基因的环境污染[14][15]

8. 要点

  • 全球抗生素的消耗量是每天数十亿剂量,而且还在增加。
  • 人类和动物使用的抗生素极大地改变了它们的共生微生物群落,并筛选出了对这些分子抗性越来越强的细菌菌株。
  • 人类和动物致病菌的适应能力与其基因组可塑性有关,使得它们不断发展和交换新的抗菌药物耐药性机制。
  • 人类和动物消耗的抗生素以及具有抗菌药物耐药性机制的细菌在环境中以活性形式分布。
  • 环境是众多细菌种类和抗生素抗性基因的天然来源库,并且人源和动物源的污染使其不断丰富。
  • 在人类、动物和环境之间不断的交换,会使抗生素抗性的出现和传播长久地持续下去。
  • 有必要开发新的抗生素和新的治疗策略来抵御抗生素抗性,并减少和优化目前人类和动物的抗生素使用量。

 


参考资料及说明

封面图片:在测试抗生素敏感性之前,在选择性培养基上分离细菌菌落。[来源:Getty Images, royalty-free.]

[1] 一个可移动的遗传元件是基因组中位置不固定的部分。这些元素是由1983年获得诺贝尔生理学或医学奖的美国细胞遗传学家芭芭拉·麦克林托克发现的。它们种类繁多,包括质粒、转座子、整合子。

[2] 一个生物体整合来自另一个生物体的遗传物质而不是其后代的过程(也称为横向基因转移)。 基因工程的很大一部分由基因的人工水平转移组成。

[3] Pendleton JN, Gorman SP, Gilmore BF. (2013). Clinical relevance of the ESKAPE pathogens. Expert Rev Anti Infect Ther. 11(3):297‑308.

[4] Finley RL, Collignon P, Larsson DGJ, McEwen SA, Li X-Z, Gaze WH, et al (2013). The scourge of antibiotic resistance: the important role of the environment. Clin Infect Dis, 57(5):704-10.

[5] D’Costa VM, King CE, Kalan L, Morar M, Sung WWL, Schwarz C, et al (2011). Antibiotic resistance is ancient. Nature. 477(7365):457‑61.

[6] Cantón R. (2009). Antibiotic resistance genes from the environment: a perspective through newly identified antibiotic resistance mechanisms in the clinical setting. Clin Microbiol Infect. 15 Suppl 1:20-5.

[7] Larsson DGJ. (2014). Antibiotics in the environment. Ups J Med Sci. 119(2):108-12

[8] Singer AC, Shaw H, Rhodes V, Hart A. (2016). Review of Antimicrobial Resistance in the Environment and Its Relevance to Environmental Regulators. Microbiol Front. 7:1728.

[9] Lekshmi M, Ammini P, Kumar S, Varela MF. (2017). The Food Production Environment and the Development of Antimicrobial Resistance in Human Pathogens of Animal Origin. Microorganisms. 5(1).

[10] Hosein IK, Hill DW, Jenkins LE, Magee JT. (2002). Clinical significance of the emergence of bacterial resistance in the hospital environment. J Microbiol application, 92 Suppl:90S-7S.

[11] Le-Minh N, Khan SJ, Drewes JE, Stuetz RM. (2010). Fate of antibiotics during municipal water recycling treatment processes. Water Res. 44(15):4295-323.

[12] Nesme J, Cécillon S, Delmont TO, Monier J-M, Vogel TM, Simonet P. (2014). Large-scale metagenomic-based study of antibiotic resistance in the environment. Curr Biol, 24(10):1096-100.

[13] Zurek L, Ghosh A. (2014). Insects represent a link between food animal farms and the urban environment for antibiotic resistance traits. Appl About Microbiol. 80(12):3562-7.

[14] Pruden A, Larsson DGJ, Amézquita A, Collignon P, Brandt KK, Graham DW, et al (2013). Management options for reducing the release of antibiotics and antibiotic resistance genes to the environment. About Health Perspect. 121(8):878‑85.

[15] Laxminarayan R, Duse A, Wattal C, Zaidi AKM, Wertheim HFL, Sumpradit N, et al (2013). Antibiotic resistance-the need for global solutions. Lancet Infect Dis. 13(12):1057-98.


环境百科全书由环境和能源百科全书协会出版 (www.a3e.fr),该协会与格勒诺布尔阿尔卑斯大学和格勒诺布尔INP有合同关系,并由法国科学院赞助。

引用这篇文章: MAURIN Max (2024年3月9日), 抗生素,抗生素耐药性与环境, 环境百科全书,咨询于 2024年12月9日 [在线ISSN 2555-0950]网址: https://www.encyclopedie-environnement.org/zh/sante-zh/antibiotics-antibiotic-resistance-and-environment/.

环境百科全书中的文章是根据知识共享BY-NC-SA许可条款提供的,该许可授权复制的条件是:引用来源,不作商业使用,共享相同的初始条件,并且在每次重复使用或分发时复制知识共享BY-NC-SA许可声明。

Antibiotics, antibiotic resistance and environment

antibiorésistance - antibiotiques - antibiotics - antibiotics resistance

Microorganisms naturally produce antibiotics that inhibit the growth of other competing microorganisms. To survive, they develop genetic and biochemical mechanisms of antibiotic resistance, which have spread widely between species due to their frequent genetic exchanges. However, since the 1940s, humans have developed new antibiotics, and their use has become massive: in 15 years, global antibiotic consumption has increased by 65%, mainly in middle- and low-income countries. This global phenomenon is now a major public health concern. Some bacteria that are pathogenic to humans and animals have become resistant to most of the antibiotic molecules developed by the pharmaceutical industry. In addition, antibiotics administered to humans and animals, and resistant bacteria selected from these hosts, have been widely disseminated in the environment. Bacteria have also evolved towards an increase in their antibiotic resistance capacities. There are permanent exchanges between bacterial flora in environmental, animal or human reservoirs. The fight against antibiotic resistance must therefore be considered comprehensively. Shouldn’t it take into account the effects of antibiotics on these different reservoirs?

1. Antimicrobial resistance in bacteria: A global health threat

bacterial resistance mechanisms
Figure 1. Antibiotic target and bacterial resistance mechanisms. This diagram presents the main bacterial targets of antibiotics and the primary mechanisms of bacterial resistance to antibiotics. In each case the families of antibiotics concerned are listed. [Source: Creative Commons Attribution 2.0 Generic License.]
A figure alerts researchers to the consequences of the risk of antibiotic resistance on public health: 42.3 billion daily doses of antibiotics were consumed worldwide in 2015. Antimicrobial resistance is defined as the ability of certain bacteria to resist the action of one or more antibiotics. It corresponds to the presence in the genome of these bacteria of genes encoding this resistance. Four main biochemical mechanisms are responsible for bacterial resistance to a given antibiotic:

  • the impermeability of the bacterial membrane to this antibiotic;
  • the efflux of the antibiotic out of the bacterium after penetration;
  • the reduction of the antibiotic’s affinity for its bacterial target(s), by quantitative or qualitative modification of the latter;
  • and the inactivation of the antibiotic by bacterial enzymes.

conjugation and transduction -
Figure 2. Conjugation and transduction. Conjugation (left). 1. The donor bacterium has a conjugative plasmid that the recipient bacterium does not have. 2. The donor bacterium establishes contact with the recipient bacterium through pili. 3. The donor bacterium replicates its plasmid and transfers it to the recipient bacterium. 4. The recipient bacterium has acquired new plasmid genes and is itself becoming a donor bacterium. Transduction (right). 1. A virus (bacteriophage) infects a bacterium. 2. Incorporation of the viral genome into the bacterial genome and viral replication. 3. Encapsidation of the virus that incorporates fragments of the bacterial genome. 4. infection by this bacteriophage of a new bacterium. 5. the virus transmits the fragment of the bacterial genome from the donor bacterium to the recipient bacterium. 6. The recipient bacterium integrates the donor bacterial fragment which then gives it new properties (virulence, antibiotic resistance, etc.). [Source: On the left, translated from: By derivative work: Franciscosp2 (talk) Bacterial_Conjugation_en.png: Mike Jones (Bacterial_Conjugation_en.png) [CC BY-SA 2.5], via Wikimedia Commons ; On the right, By Reytan with modifications by Geni & Toony (common Image:Transduction (genetics)en.svg) [Public domain], via Wikimedia Commons.]
Figure 1 schematically presents the targets of antibiotics and the mechanisms of bacterial resistance to these molecules.

In some bacterial species, these antimicrobial resistance mechanisms are stable and affect most strains: we speak of natural antimicrobial resistance. On the contrary, acquired antibiotic resistance occurs when certain strains of a bacterial species usually susceptible to an antibiotic acquire a genetic mechanism of resistance to it. The acquisition of new antibiotic resistance may be linked to mutations (see Genetic Polymorphism and Variation) affecting the properties or level of expression of resistance genes. It may also be the consequence of the acquisition of new resistance genes. Indeed, mobile genetic elements [1] (plasmids, transposons, integrons, etc.) can be exchanged between bacteria of the same species or of different species. These exchanges take place through horizontal gene transfer mechanisms [2] (conjugation, transformation, transduction, transposition) (Figures 2 and 3). All antibiotic resistance genes present in pathogenic or non-pathogenic microorganisms constitute the resistome.

transformation and transposition
Figure 3. Transformation and transposition. Transformation (left). I. Bacterium A releases a gene in its environment (active mechanism or lysis of the bacterium). II. The B bacterium captures and incorporates this foreign gene into its cytoplasm. III. The bacterium B integrates this gene into its genome (a plasmid gene in this example). IV. The bacterium B has a new gene encoding, for example, antibiotic resistance. Transposition (right). 1. A donor DNA contains a transposon framed by two insertion sequences (IS). This transposon can contain several genes encoding variable functions (virulence, antibiotic resistance, etc.). 2. The enzyme transposase binds to the IS. 3. A transposition complex is formed. 4. The transposon is excised. 5. This transposon moves to a target DNA site, either on the same replicon (chromosome or plasmid) or on another replicon (e. g. transfer from the chromosome to a plasmid). 6. The transposon is inserted into the target DNA, giving it new properties. [Source: On the left, adapted from: By Sprovenzano15 [CC BY-SA 3.0], from Wikimedia Commons; right, adapted from Alana Gyemi [CC BY-SA 4.0], from Wikimedia Commons.]
The massive use of antibiotics over the past eight decades has led to the selection and interspecies transfer of new antibiotic resistance mechanisms. The accumulation of these resistances in the same bacterium leads to multidrug resistance (resistance to several families of antibiotics, MDR) or even total resistance (resistance to all available antibiotics). These two situations can lead to therapeutic impasses. Some bacterial species frequently involved in human pathology and often resistant to multiple antibiotics have been grouped under the anagram “ESKAPE” [3]. These are Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, Enterobacter and more recently other Enterobacteriaceae (Table 1).

Antimicrobial resistance is currently a major global public health problem that has required the development of international (including WHO) and national control plans. While the human and animal reservoirs of these antibiotic resistances are well characterized, the role of the environment in their emergence and spread has only recently been recognized.

2. The environment: an old antibiotic resistance reservoir

Many environmental microorganisms (mainly bacteria and fungi) naturally produce antibiotics, which give them a selective growth advantage over other environmental species. These microorganisms possess genes encoding antibiotic resistance mechanisms to the antibiotics they produce. They can transmit these resistance genes to their offspring (vertical transmission) [4]. Microorganisms that do not produce antibiotics may also naturally harbour antibiotic resistance genes or acquire them de novo. In bacteria, there are many genetic exchanges between individuals of the same or different species (horizontal transmission). The spread of antimicrobial resistance between bacteria living in the environment is probably very old (several billion years) and continues today [5]. These resistances can be transmitted from environmental bacteria to those that colonize humans and animals. Examples include the recent emergence of extended-spectrum beta-lactamases (ESBLs) of the CTX-M type or a new mechanism for resistance to fluoroquinolones (qnr genes) [6].

3. Release of human-made antibiotics into the environment

The beginning of the 20th century was marked by the discovery and especially the mass production of natural antibiotics (extracts of microorganisms that produce these molecules) or obtained by chemical synthesis. Natural antibiotics include beta-lactam antibiotics (including penicillin), aminoglycosides, tetracyclines, and macrolides. Most of these natural molecules have been chemically modified to become semi-synthetic and more recently synthetic antibiotics. Sulphonamides and quinolones are molecules that have been immediately synthesized by humans. From the 1940s to nowadays, antibiotic use in humans and animals has increased exponentially, corresponding to the release of millions of tons of antibiotics into the environment. There are three main sources of environmental pollution by antibiotics:

  • industrial antibiotic production plants that disperse part of this production in their aquatic environment;
  • the breeding of domestic animals treated with antibiotics;
  • humans who receive antibiotics.

3.1. Antibiotic production plants

Antibiotic production plants release large quantities of antibiotics in their effluents. Current regulatory constraints in terms of environmental pollution are insufficient in countries producing large quantities of antibiotics, particularly in Europe, the United States, China, and India. Antibiotic concentrations that may exceed 1 mg/L have been detected in effluents from some production plants [7]. These concentrations have a significant impact on the environmental microbial flora. Also, these antibiotics spread widely in the environment and pollute groundwater.

3.2. Veterinary use of antibiotics

Antibiotic use in domestic animals (wild animals are rarely involved) accounts for about 60% of total antibiotic production and continues to increase [8]. More than 100,000 tons of antibiotics are administered annually worldwide to livestock, lowland animals and aquaculture [9]. Tetracyclines in particular, followed by penicillins and sulfonamides, are the most commonly used antibiotics. However, beta-lactam antibiotics, aminoglycosides, phenicols, macrolides and glycopeptides are also concerned. Antibiotics used in humans and animals belong to the same families and are therefore inactivated by the same antimicrobial resistance mechanisms. Antibiotics are administered to domestic animals to treat infectious diseases, to prevent them (antibiotic prophylaxis), or as food supplements. For the treatment and prophylaxis of bacterial infections, antibiotics are often dispensed in drinking water or feed to the entire farm, even if only a few animals are sick. The systematic use of antibiotics as feed supplements (especially livestock, poultry, fish, etc.) is intended to improve livestock productivity (in terms of the amount of meat produced, for example).

This use of antibiotics for profitability purposes has been the overwhelming majority for several decades. It is currently banned in Europe, but its use persists in many countries. It is recognized as a major cause of antibiotic resistance in bacteria (e. g. Escherichia coli) colonizing the digestive tract of these animals. Most of the resistant bacteria selected in these animals can then be transmitted to humans through contact with them or through contaminated food products. Besides, antibiotics administered to animals are present in an active form in their feces. Wastewater from these farms is often directly released into the aquatic environment or used to irrigate crops without prior treatment.

3.3. Antibiotic use in humans

Antibiotics are used in humans, either to treat infectious diseases or to prevent them (antibiotic prophylaxis). Global human consumption of antibiotics corresponds to several tens of billions of unit doses each year. Beta-lactam antibiotics (penicillins, cephalosporins, carbapenems) are currently the most widely used antibiotics (about 60% of human consumption). The use of tetracyclines, macrolides, and fluoroquinolones is also high. About 80% of antibiotics are used in the community and 20% in hospitals. However, the role of health care institutions in the spread of bacterial resistance is major due to the broad spectrum of antibiotics used and the high risk of human-to-human transmission of selected resistant bacteria [10]. Some of the antibiotics prescribed to infected people are not used and are therefore released with our daily waste into the environment.

More significantly, most antibiotics absorbed by humans are eliminated in active form in urine and faeces. In developing countries, these antibiotics are directly dispersed in the hydro-telluric environment. In countries with wastewater treatment infrastructures, a large proportion of these antibiotics are found in wastewater treatment plants [11]. Concentrations in the order of µg/L of antibiotics (beta-lactam antibiotics, macrolides, tetracyclines, fluoroquinolones, etc.) have been detected in wastewater from some treatment plants. These antibiotics are biodegraded, absorbed in sewage sludge, or eliminated unchanged in the plant effluent. Sewage sludge can be used as fertilizer in crop fields, while effluent is discharged into the aquatic environment (rivers). In both cases, the active antibiotics are then released into the hydro-telluric environment.

  • Residual concentrations of antibiotics in the environment

Antibiotics are detected in some aquatic and terrestrial environments at concentrations ranging from ng to µg per litre of water or per gram of soil. Similar concentrations have also been measured in some groundwater. These antibiotics persist in the environment after contamination for periods that can range from a few days (e.g., beta-lactam antibiotics) to several months (e.g., fluoroquinolones and tetracyclines). Therefore, for the latter molecules, there is an accumulation phenomenon if environmental contamination is permanent or frequent. Antibiotic residues can also be detected in the marine environment. Finally, residual concentrations of antibiotics in the order of ng/L have sometimes been detected in drinking water.

4. Release of novel antibiotic resistance genes of human and animal origin into the environment

Antibiotics administered to humans and animals select from their commensal flora (their microbiota) the bacterial species and strains most resistant to these molecules (see Human microbiots: Allies for our health).

Antibiotics also promote gene mutations and horizontal gene transfers encoding antibiotic resistance by induction in bacterial SOS systems. This phenomenon is particularly important in the intestinal microbiota, which is rich and contains several thousand bacterial species (Figure 4).

intestinal microbiota - digestive tract
Figure 4. The microbiota of the digestive tract. The microbiota is rich and varied in the oral cavity and oro-pharynx, then at the end of the ileum and in the colon. It is poor in the stomach due to the very acidic environment. Anaerobic bacteria (which multiply in the absence of oxygen) predominate widely in the colon. [Source: Adapted from By Mariana Ruiz, Jmarchn, Translated in French by Moez [Public domain], from Wikimedia Commons.]
Man and animals spread in the environment the bacteria that constitute their commensal flora, especially those carrying antibiotic resistance genes. Some bacterial species can survive for a long time in the environment (water, soil, soiled objects, etc.). Wastewater treatment plants, where a large part of wastewater is concentrated due to human activities, concentrate a large number of antibiotic-resistant bacteria and their resistance genes. Heavily contaminated sludge is often used to fertilize agricultural land. Purified but unsuitable water is released into the environment while it is still loaded with bacteria and antibiotic resistance genes. These wastewater treatment plants are therefore a major source of environmental pollution by new antibiotic resistance genes.

5. Emergence of new antibiotic-resistant products in the environment

The hydro-telluric environment is a medium rich in microorganisms whose diversity is only partially characterized. Concerning bacteria, recent metagenomic studies have led to the discovery of many new species. They also showed that more than 99% of environmental bacterial species are not cultivable with current methods [12].

This environment is increasingly polluted by bacteria resistant to antibiotics of human or animal origin, by genes encoding these resistances, and by human-made antibiotics. Plants absorb some of these antibiotics, particularly in crops irrigated with water or enriched with sludge from wastewater treatment plants contaminated by these molecules. While residual antibiotic concentrations in the environment are usually low, they nevertheless exert a progressively increasing selection pressure on the natural microbial flora. This selection pressure promotes horizontal exchanges of antibiotic resistance genes between natural and polluting species, particularly in the rich and varied bacterial populations located in biofilms. The natural predators of these microorganisms, the protozoa that are free-living organisms (amoebas in particular), also promote these genetic exchanges.

All in all, all the conditions are in place for new antibiotic resistance to emerge in the environment, both in the natural environmental bacterial flora, but also in the human and animal flora capable of surviving in this environment.

6. The environment as a source of new antibiotic resistance in humans and animals

Microorganisms from their hydro-telluric environment frequently colonize humans and animals. This colonization can be direct through contact with this environment during daily activities or indirect through ingestion of contaminated drinking water or food, or exposure to soiled objects etc.) [13]. The commensal microbial flora of humans and animals acts as a microbial barrier that protects against infection by less well adapted exogenous species. Nevertheless, many human and animal bacterial species survive in the environment and can, therefore, re-contaminate these hosts. On the other hand, environmental reservoir microorganisms can colonize the skin and mucous membranes of humans and animals. This colonization can be transient and of short duration (a few hours or days) or prolonged (a few weeks to several months or even years). During this period of colonization, genetic exchanges between this exogenous flora and the endogenous commensal flora can occur. These exchanges are particularly important at the level of the digestive microbiota, due to the richness and diversity of this microbiota, but also the prolonged duration of intestinal carriage of many environmental microorganisms after their ingestion.

It should be noted that antibiotic-resistant bacteria are also often resistant to antiseptics. These include heavy metals (silver, copper, mercury, etc.) and biocides (ethanol, formaldehyde, chlorhexidine, triclosan, quaternary ammonium, etc.). Environmental pollution by antiseptics can contribute to the selection of microorganisms that carry antibiotic resistance. Two phenomena make it possible to understand that an antiseptic selects strains carrying antibiotic resistance (or that an antibiotic selects for resistance to an antiseptic):

  • the genetic mechanisms of resistance to an antibiotic and an antiseptic are carried by the same genetic carriers (plasmids in particular); exposure of a bacterium to the antibiotic or antiseptic concerned selects the strains carrying resistance to both types of compounds: it is co-resistance ;
  • the same genetic mechanism (encoding an efflux pump, for example) leads to resistance to both an antibiotic and an antiseptic; it is the phenomenon of cross-resistance that leads to the selection of both types of resistance in the presence of one or the other of these molecules.

7. Synthesis and perspectives: A better understanding of the risks associated with the environment and intensive livestock farming

environmental pollution by antibiotics - antibiotics
Figure 5. Environmental pollution by antibiotics, antibiotic-resistant bacteria, and their resistance genes. The commensal and pathogenic bacterial flora of humans and animals (livestock, poultry, farmed fish, etc.) is under pressure from antibiotic selection in the community, care facilities, and livestock. Bacteria selected for their resistance to antibiotics are spread in the environment, directly or via wastewater treatment plants. These resistant bacteria diffuse between human and animal reservoirs (direct contact, food, etc.). The environment itself is a source of new antibiotic resistance in bacteria that can contaminate humans and animals.

Antimicrobial resistance is a complex and long-standing phenomenon, which has become a major problem for human and animal health due to the combined effects of three actors: 1/ overconsumption of antibiotics for several decades; 2/ high genomic plasticity and therefore  adaptability of bacteria to the selection pressure exerted by these molecules; and 3/ permanent exchanges between the three major reservoirs of resistance genes: the environment, animals and humans (Figure 5).

The numerous and rapid international trade (human, animal, food) has also aggravated this situation. The environment is polluted by both resistant microorganisms of human and animal origin, and by residual concentrations of antibiotics. These two types of pollution promote the emergence of new antibiotic resistance and their transfer between bacterial species.

Due to the very strong interactions between human, animal and environmental reservoirs, the spread of genetic mechanisms of antimicrobial resistance is a rapid and major phenomenon. Compared to other environmental pollutants (other drugs, chemicals, heavy metals, etc.), this pollution is characterized by its possible spread among the human and animal population. Indeed, the inter-human, inter-animal, and human-animal transmissions of antibiotic-resistant bacteria explain the individual but also the collective effects of this pollution. Among the means of combating the emergence and spread of antimicrobial resistance, it is essential in particular:

  • to reduce and optimize overall antibiotic consumption;
  • to avoid or at least limit the spread of antibiotics and bacteria carrying resistance genes in the environment, in particular from significant sources (hospitals, antibiotic manufacturing plants, intensive livestock farming, water treatment plants, etc.);
  • to improve the level of hygiene and develop water purification systems in developing countries;
  • to better monitor environmental pollution by antibiotics and antibiotic resistance genes [14], [15].

8. Messages to remember

  • Global consumption of antibiotics is in the billions of daily doses and is increasing.
  • Antibiotics consumed by humans and animals profoundly modify their commensal microbial flora and select bacterial strains that are increasingly resistant to these molecules.
  • The adaptive capacities of human and animal pathogenic bacteria linked to their genomic plasticity allow them to develop and exchange new antimicrobial resistance mechanisms continually.
  • Antibiotics consumed by humans and animals, as well as bacteria carrying antimicrobial resistance mechanisms, are dispersed in the environment in active form.
  • The environment is a natural reservoir of many bacterial species and antibiotic resistance genes, enriched continuously by pollution from human and animal sources.
  • Permanent exchanges between human, animal and environmental reservoirs perpetuate the emergence and spread of antibiotic resistance
  • It is necessary to develop new antibiotics and new therapeutic strategies to combat antibiotic resistance, but also to reduce and optimize the consumption of current antibiotics in humans and animals.

 


References and notes

Cover image. Isolation of a bacterial colony on a selective medium, before testing for antibiotic sensitivity. [Source: Getty Images, royalty-free.]

[1] A mobile genetic element is a segment of the genome whose position is not fixed. These elements were discovered by the American cytogeneticist Barbara McClintock, who won the Nobel Prize in Physiology or Medicine in 1983. There is a wide variety of them, including plasmids, transposons, integrons.

[2] A process in which an organism integrates genetic material from another organism without being its descendant (also called lateral gene transfer). A large part of genetic engineering consists of the artificial horizontal transfer of genes.

[3] Pendleton JN, Gorman SP, Gilmore BF. (2013). Clinical relevance of the ESKAPE pathogens. Expert Rev Anti Infect Ther. 11(3):297‑308.

[4] Finley RL, Collignon P, Larsson DGJ, McEwen SA, Li X-Z, Gaze WH, et al (2013). The scourge of antibiotic resistance: the important role of the environment. Clin Infect Dis, 57(5):704-10.

[5] D’Costa VM, King CE, Kalan L, Morar M, Sung WWL, Schwarz C, et al (2011). Antibiotic resistance is ancient. Nature. 477(7365):457‑61.

[6] Cantón R. (2009). Antibiotic resistance genes from the environment: a perspective through newly identified antibiotic resistance mechanisms in the clinical setting. Clin Microbiol Infect. 15 Suppl 1:20-5.

[7] Larsson DGJ. (2014). Antibiotics in the environment. Ups J Med Sci. 119(2):108-12

[8] Singer AC, Shaw H, Rhodes V, Hart A. (2016). Review of Antimicrobial Resistance in the Environment and Its Relevance to Environmental Regulators. Microbiol Front. 7:1728.

[9] Lekshmi M, Ammini P, Kumar S, Varela MF. (2017). The Food Production Environment and the Development of Antimicrobial Resistance in Human Pathogens of Animal Origin. Microorganisms. 5(1).

[10] Hosein IK, Hill DW, Jenkins LE, Magee JT. (2002). Clinical significance of the emergence of bacterial resistance in the hospital environment. J Microbiol application, 92 Suppl:90S-7S.

[11] Le-Minh N, Khan SJ, Drewes JE, Stuetz RM. (2010). Fate of antibiotics during municipal water recycling treatment processes. Water Res. 44(15):4295-323.

[12] Nesme J, Cécillon S, Delmont TO, Monier J-M, Vogel TM, Simonet P. (2014). Large-scale metagenomic-based study of antibiotic resistance in the environment. Curr Biol, 24(10):1096-100.

[13] Zurek L, Ghosh A. (2014). Insects represent a link between food animal farms and the urban environment for antibiotic resistance traits. Appl About Microbiol. 80(12):3562-7.

[14] Pruden A, Larsson DGJ, Amézquita A, Collignon P, Brandt KK, Graham DW, et al (2013). Management options for reducing the release of antibiotics and antibiotic resistance genes to the environment. About Health Perspect. 121(8):878‑85.

[15] Laxminarayan R, Duse A, Wattal C, Zaidi AKM, Wertheim HFL, Sumpradit N, et al (2013). Antibiotic resistance-the need for global solutions. Lancet Infect Dis. 13(12):1057-98.


环境百科全书由环境和能源百科全书协会出版 (www.a3e.fr),该协会与格勒诺布尔阿尔卑斯大学和格勒诺布尔INP有合同关系,并由法国科学院赞助。

引用这篇文章: MAURIN Max (2019年5月7日), Antibiotics, antibiotic resistance and environment, 环境百科全书,咨询于 2024年12月9日 [在线ISSN 2555-0950]网址: https://www.encyclopedie-environnement.org/en/health/antibiotics-antibiotic-resistance-and-environment/.

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