靶向鲍曼不动杆菌耐药结节部外排泵转录调控因子对抗抗生素耐药性-动脉网

Targeting Acinetobacter baumannii resistance-nodulation-division efflux pump transcriptional regulators to combat antimicrobial resistance

Nature 等信源发布 2025-01-25 19:21

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Abstract

摘要

Regulatory elements controlling gene expression fine-tune bacterial responses to environmental cues, including antimicrobials, to optimize survival.

控制基因表达的调控元件微调细菌对环境线索（包括抗菌剂）的反应，以优化生存。

Acinetobacter baumannii

鲍曼不动杆菌

, a pathogen notorious for antimicrobial resistance, relies on efficient efflux systems. Though the role of efflux systems in antibiotic expulsion are well recognized, the regulatory mechanisms controlling their expression remain understudied. This review explores the current understanding of these regulators, aiming to inspire strategies to combat bacterial resistance and improve therapeutic outcomes..

，一种因抗微生物耐药性而臭名昭著的病原体，依赖于有效的外排系统。尽管外排系统在抗生素排出中的作用已得到公认，但控制其表达的调控机制仍未得到充分研究。本综述探讨了目前对这些监管机构的理解，旨在激发对抗细菌耐药性和改善治疗效果的策略。。

Antimicrobial resistance (AMR) is a critical global health threat as bacteria are increasingly able to evade antibiotics used for the medical treatment of infections. In 2021, an estimated 1.14 million deaths were directly attributed to untreatable multidrug resistant (MDR) bacteria; as it is possible that all cases were not identified or reported, this death toll could be higher.

抗菌药物耐药性（AMR）是一个严重的全球健康威胁，因为细菌越来越能够逃避用于治疗感染的抗生素。2021年，估计有114万人死亡直接归因于无法治疗的多药耐药（MDR）细菌；由于所有病例都可能未被发现或报告，因此死亡人数可能会更高。

. It has been estimated that a total of 39.1 million people could die from AMR bacterial infections between 2025 and 2050

。据估计，在2025年至2050年间，总共有3910万人可能死于AMR细菌感染

. Clearly, there is an urgent need to look beyond the known mechanisms of antibiotic avoidance to find another way to combat MDR infections.

显然，迫切需要超越已知的抗生素避免机制，寻找另一种对抗MDR感染的方法。

The prevalence of antibiotics in the environment due to excessive and misguided use has led to more and more environmental bacteria acquiring antibiotic resistance elements (i.e., plasmids, integrons) in order to survive

由于过量和误导使用，抗生素在环境中的流行导致越来越多的环境细菌获得抗生素耐药元件（即质粒、整合子）以生存

. These environmental bacteria can then potentially evolve into clinically significant threats

这些环境细菌可能会演变为临床上重大的威胁

Acinetobacter

不动杆菌

species are a perfect example of this problem. These often harmless Gram-negative coccobacilli are prevalent in water and soil

物种就是这个问题的完美例子。这些通常无害的革兰氏阴性球菌在水和土壤中普遍存在

. However, some species have made the leap to becoming opportunistic pathogens leading to infections in the blood, wounds, and lungs of immunocompromised individuals

然而，一些物种已经跃升为机会性病原体，导致免疫功能低下个体的血液、伤口和肺部感染

. In a multi-year hospital study,

.在一项多年的医院研究中，

A. baumannii

A.鲍曼不动杆菌

was found to be the primary causative agent of

被发现是导致

Acinetobacter

不动杆菌

infections, followed by the non-

感染，其次是非感染-

baumannii

鲍曼

isolates

分离株

A. pittii

A. 皮蒂

and

和

A. nosocomialis

A. 医院

; infections with

；感染

A. haemolyticus

A、溶血性

A. johnsonii, A. junii

A. 约翰逊， A. 六月

A. calcoaceticus

A. lwoffii

A. 洛菲

A. schindleri

A. 辛德利

, and

，以及

A. ursingii

A.乌尔辛吉

A. courvalinii

A. 柯伐林

have also been reported

也有报道

. Globally,

.全球范围内，

A. baumannii

was the fifth most common AMR pathogen associated with or responsible for deaths in 2019

是2019年与死亡相关或导致死亡的第五大最常见的AMR病原体

In 2018, the World Health Organization classified

2018年，世界卫生组织将

A. baumannii

as a critical multidrug-resistant pathogen, urgently requiring new antibiotics

作为一种关键的多重耐药病原体，迫切需要新的抗生素

. According to the 2019 Global AMR Threat Report, 132,000

根据2019年全球AMR威胁报告，132000

A. baumannii

infections that were directly attributable to patient mortality were resistant to at least one clinically used antibiotic, and 57,700 lethal infections showed carbapenem resistance

直接归因于患者死亡率的感染对至少一种临床使用的抗生素具有耐药性，57700例致命感染显示碳青霉烯类耐药

. Currently, carbapenem-resistant

目前，碳青霉烯耐药

A. baumannii

(CRAB) is the main cause of nosocomial infections in intensive care units

（CRAB）是重症监护病房医院感染的主要原因

. As carbapenems—a subclass of the well-known β-lactam antibiotic family—are a primary, last-resort treatment for MDR infections, there is no effective antibiotic option to manage CRAB infections

. Moreover, there has been a notable rise in MDR among non-

baumannii Acinetobacter

鲍曼不动杆菌

species including carbapenem resistance in

A. calcoaceticus

A. pittii

A.皮蒂

A. nosocomialis

A. 医院

A. seifertii

A. 安全

, and

，以及

A. lactucae

A.乳杆菌

(formerly

A. dijkshoorniae

A.dijkshoorniae

)

. Together, these issues present an ongoing and compounding challenge that requires immediate attention and alternative solutions.

总之，这些问题构成了一个持续且复杂的挑战，需要立即关注和替代解决方案。

Challenges with

面临的挑战

Acinetobacter

不动杆菌

Whole genome sequencing studies have improved species identification within

全基因组测序研究改善了物种鉴定

Acinetobacter

不动杆菌

compared to traditional 16S rRNA amplicon-based methods revealing a greater diversity in their environmental niches and more antibiotic-resistance genes than previously thought in this genus

与传统的基于16S rRNA扩增子的方法相比，揭示了其环境生态位的更大多样性和比以前认为的该属更多的抗生素抗性基因

. Recent phylogenomic studies of

.最近的系统发育基因组学研究

Acinetobacter

不动杆菌

species reveal no distinct clustering between clinical and non-clinical isolates

物种显示临床和非临床分离株之间没有明显的聚类

. Furthermore, surveillance studies reporting the presence of

此外，监测研究报告存在

Acinetobacter

不动杆菌

drug-resistance genes outside of clinical settings, including in environmental

临床环境之外的耐药基因，包括环境中的耐药基因

and animal isolates

和动物分离株

, highlight that

，突出显示

Acinetobacter

不动杆菌

is a One Health problem

是一个健康问题

. This raises concerns about future threats from gene transfer to non-resistant species

。这引起了人们对未来从基因转移到非抗性物种的威胁的担忧

. Indeed,

.的确，

Acinetobacter

不动杆菌

species are noted for the intrinsic resistance genes found in both their core and accessory genomes

物种因其核心和辅助基因组中发现的内在抗性基因而闻名

. This intrinsic resistance, combined with significant genomic plasticity, allows

这种内在的抵抗力，再加上显着的基因组可塑性，可以

Acinetobacter

不动杆菌

species to readily acquire or lose genes and enhances their adaptability

物种容易获得或失去基因，并增强其适应性

. Such versatility also enables tolerance of extreme conditions—desiccation

这种多功能性还可以耐受极端条件下的干燥

, oxidative stress

，氧化应激

, and acidic pH

和酸性pH

—further contributing to their overall resilience.

-进一步提高了他们的整体弹性。

Efflux pumps in Acinetobacter baumannii

鲍曼不动杆菌的外排泵

Efflux pumps are membrane transporters capable of actively expelling substrates—including antimicrobial agents—into the periplasmic or extracellular environment thus preventing the substrate from reaching its intracellular target. As such, efflux pumps are often the primary defense mechanism against antimicrobial compounds, though other protective mechanisms can be engaged (i.e., enzymatic modification of the drug, target site mutation, reduced membrane permeability).

外排泵是膜转运蛋白，能够将包括抗菌剂在内的底物主动排出到周质或细胞外环境中，从而阻止底物到达其细胞内靶标。因此，外排泵通常是抗微生物化合物的主要防御机制，尽管可以采用其他保护机制（即药物的酶促修饰，靶位点突变，膜通透性降低）。

. Increased expression of efflux pumps alone can effectively confer multidrug resistance as many of the pumps are capable of expelling a diverse range of structurally dissimilar drugs

。单独增加外排泵的表达可以有效地赋予多药耐药性，因为许多泵能够排出多种结构不同的药物

Different efflux pump families have been identified in

不同的外排泵系列已在

Acinetobacter

不动杆菌

species including multidrug and toxic compound extrusion (MATE), ATP-binding cassette (ABC), proteobacterial antimicrobial compound efflux (PACE), major facilitator superfamily (MFS), small multidrug resistance (SMR), and resistance-nodulation-division (RND) pumps

物种包括多药和有毒化合物挤出（MATE），ATP结合盒（ABC），变形杆菌抗菌化合物外排（PACE），主要促进因子超家族（MFS），小多药耐药性（SMR）和耐药性结瘤部门（RND）泵

. The most clinically relevant efflux pump family with respect to AMR infections caused by

Acinetobacter

不动杆菌

species is the RND pumps

物种是RND泵

. Since the expression of these pumps is typically tightly regulated, strategies that target these controlling regulatory pathways could be key to preventing overexpression of efflux pump genes and consequently impairing removal of toxic compounds

由于这些泵的表达通常受到严格调控，因此针对这些控制调控途径的策略可能是防止外排泵基因过度表达并因此损害有毒化合物去除的关键

. This approach may pave the way for the development of new antimicrobial compounds in the form of drugs that limit efflux pump gene expression which in turn make the bacteria more susceptible to other assaults.

这种方法可能为开发新的抗菌化合物铺平道路，这些化合物的形式是限制外排泵基因表达的药物，从而使细菌更容易受到其他攻击。

Understanding the regulation of RND efflux pumps

了解RND外排泵的调节

Spanning the inner and outer membranes, RND efflux systems are typically comprised of an inner membrane RND transporter, a periplasmic adapter protein (PAP), and an outer membrane factor (OMF). The PAP and the RND transporter genes are typically encoded as a single operon which may or may not include the OMF gene.

RND外排系统跨越内膜和外膜，通常由内膜RND转运蛋白，周质衔接蛋白（PAP）和外膜因子（OMF）组成。PAP和RND转运蛋白基因通常被编码为单个操纵子，其可能包括也可能不包括OMF基因。

. They form a continuous channel across the cell wall of Gram-negative bacteria thereby facilitating the extrusion of its substrates directly to the extracellular environment

它们在革兰氏阴性菌的细胞壁上形成一个连续的通道，从而促进其底物直接挤出到细胞外环境中

. RND efflux pumps have a broad substrate specificity and so contribute significantly to the MDR phenotype

RND外排泵具有广泛的底物特异性，因此对MDR表型有重要贡献

在

Acinetobacter

不动杆菌

species, a total of nine RND family transporters have been identified

物种，共鉴定出9种RND家族转运蛋白

of which the most clinically relevant efflux pumps are AdeAB(C), AdeIJK, and AdeFGH (Table

其中临床上最相关的外排泵是AdeAB（C），AdeIJK和AdeFGH（表

). (Note that not all

)。（请注意，并非所有

Acinetobacter

不动杆菌

species have AdeC; AdeAB(C) indicates that AdeC may be present.) Of these three, overexpression of

物种有AdeC；AdeAB（C）表示AdeC可能存在。）在这三个中，过表达

adeAB(C)

adeAB（C）

is most commonly seen in MDR clinical isolates

最常见于MDR临床分离株

. Present in the core genome of all

Acinetobacter

不动杆菌

species, AdeIJK is believed to be the ancestral efflux pump of this genus

物种，AdeIJK被认为是该属的祖先外排泵

. AdeFGH is the least studied efflux pump, with its full clinical relevance yet to be determined

AdeFGH是研究最少的外排泵，其全部临床相关性尚待确定

Table 1 Clinically important RND efflux pumps of

表1临床上重要的RND外排泵

A. baumannii

: a summary of their substrates, regulatory elements, effectors of the regulatory elements, and potential roles of the regulators

：总结其底物，调节元件，调节元件的效应器以及调节器的潜在作用

Full size table

全尺寸表

Increased expression of efflux pump genes is a key determinant in shaping the antimicrobial resistance phenotype

外排泵基因表达的增加是形成抗菌药物耐药表型的关键决定因素

. Specific activators and repressors mainly control expression at the transcriptional level, but there is also evidence of some crosstalk between the regulators such that the expression of efflux pump operons may be influenced in multiple ways

特异性激活因子和抑制因子主要控制转录水平的表达，但也有证据表明调节因子之间存在一些串扰，因此外排泵操纵子的表达可能受到多种方式的影响

. Specifically, the response regulator AdeR of the AdeSR two-component system may potentially interact with the BaeS histidine kinase of the BaeSR two-component system to induce

具体而言，AdeSR双组分系统的反应调节剂AdeR可能与BaeSR双组分系统的BaeS组氨酸激酶相互作用以诱导

adeAB(C)

adeAB（C）

expression

表达

(both systems discussed in the section below) (Fig.

（以下部分讨论了这两种系统）（图）。

). Notably, the deletion of one efflux pump often results in the upregulation of another, underscoring the need for a comprehensive understanding of their regulatory networks

)。值得注意的是，删除一个外排泵通常会导致另一个外排泵的上调，这强调了需要全面了解其监管网络

. The primary regulatory mechanisms of the three most clinically relevant RND pumps in

。三种临床上最相关的RND泵的主要调节机制

Acinetobacter

不动杆菌

species are very distinct from each other: AdeAB(C) and AdeFGH have dedicated local regulators, whereas the regulator of AdeIJK is quite distant from the operon. Global regulators involved in altering the expression of each of the efflux pumps, which are equally as important as the specific regulators, remain poorly understood.

物种彼此非常不同：AdeAB（C）和AdeFGH有专门的当地监管机构，而AdeIJK的监管机构与操纵子相距甚远。参与改变每个外排泵表达的全球监管机构仍然知之甚少，这些外排泵与特定监管机构同样重要。

Fig. 1: Regulatory pathways of RND efflux pump operons in

图1:RND外排泵操纵子的调节途径

A. baumannii

adeIJK,

阿德伊克，

B类

adeFGH,

adeFGH，

and

和

C级

adeAB(C)

adeAB（C）

pump encoding operons. AdeFGH efflux pumps in

泵编码操作。AdeFGH外排泵

A. baumannii

A.鲍曼不动杆菌

. Solid arrows represent activation of expression, while blunt-ended arrows indicate repression of transcription. Dashed lines denote mechanisms of activation or repression that are not yet fully understood. The effectors for upregulation and downregulation of efflux pump operons are listed in boxes, with green and red arrows indicating upregulation and downregulation, respectively.

实心箭头表示表达的激活，而钝端箭头表示转录的抑制。虚线表示尚未完全理解的激活或抑制机制。框中列出了外排泵操纵子上调和下调的效应子，绿色和红色箭头分别表示上调和下调。

For example, polyunsaturated fatty acids (PUFA) and (p)ppGpp upregulate the expression of AdeIJK, whereas pleural fluid (PF) and human serum albumin (HSA) downregulate it. Additionally, the figure highlights five druggable targets (I, II, III, IV, and V) of two-component systems that could potentially modulate efflux gene expression.

例如，多不饱和脂肪酸（PUFA）和（p）ppGpp上调AdeIJK的表达，而胸水（PF）和人血清白蛋白（HSA）下调AdeIJK的表达。此外，该图突出显示了五个可药用靶标（I，II，III，IV和V）可能调节外排基因表达的双组分系统。

Created in BioRender. Kumar, A. (2024)

在BioRender中创建。库马尔，A.（2024）

https://BioRender.com/z94p008

Full size image

全尺寸图像

Regulation of AdeAB(C)

AdeAB(C)法规

AdeAB(C) is the often-overexpressed efflux pump operon in clinical isolates with the MDR phenotype

AdeAB（C）是MDR表型临床分离株中常过度表达的外排泵操纵子

. The dedicated regulator controlling the activation of

.控制激活的专用调节器

adeAB(C)

adeAB（C）

expression is AdeSR, a two-component system (TCS) regulator consisting of a membrane-spanning histidine kinase (AdeS) and a cytoplasmic response regulator (AdeR)

表达是AdeSR，一种由跨膜组氨酸激酶（AdeS）和细胞质反应调节剂（AdeR）组成的双组分系统（TCS）调节剂

(Fig.

（图。

). The histidine kinase element detects environmental signals, including antibiotics, and undergoes a conformational change to facilitate autophosphorylation of a cytoplasmic-facing histidine residue. This phosphate group is then transferred to a well-conserved aspartate residue on the response regulator which triggers its binding to DNA.

)。组氨酸激酶元件检测环境信号，包括抗生素，并经历构象变化以促进面向细胞质的组氨酸残基的自磷酸化。然后将该磷酸基团转移到响应调节剂上保守的天冬氨酸残基上，从而触发其与DNA的结合。

. AdeSR is the most studied RND efflux system regulator thus far as the structure of AdeR has been solved

就AdeR的结构而言，AdeSR是研究最多的RND外排系统调节器

and binding site of AdeR to DNA is known

AdeR与DNA的结合位点是已知的

. AdeR is unique compared to other response regulators in that it binds within the intercistronic region between

adeR

阿德尔

and

和

adeA

instead of within the defined promoter region of

而不是在定义的启动子区域内

adeAB(C)

adeAB（C）

, possibly facilitating recruitment of the σ subunit of RNA polymerase and activating downstream gene expression

. AdeR is also able to bind DNA without activation by phosphorylation allowing for the low-level, basal expression of AdeAB(C)

AdeR还能够结合DNA而不被磷酸化激活，从而允许AdeAB（C）的低水平基础表达

, and may engage in self-regulation enabling a rapid respond to external stimuli, both crucial features for survival in the sudden presence of deleterious drugs.

，并可能参与自我调节，从而能够对外部刺激做出快速反应，这两个特征对于在突然存在有害药物的情况下生存至关重要。

Studying drug-resistant isolates, researchers discovered that increased activation of AdeAB(C) was mostly due to substitutions in either the autophosphorylation site of AdeS or the receiver domain of AdeR

研究人员在研究耐药菌株时发现，AdeAB（C）的激活增加主要是由于AdeS的自磷酸化位点或AdeR的受体结构域发生了取代

. These substitutions led to enhanced sensitivity of AdeS to environmental stimuli or an increased rate of AdeR phosphorylation, respectively

这些替代分别导致ADE对环境刺激的敏感性增强或AdeR磷酸化速率增加

. Conversely, strains overexpressing AdeAB(C) due to inactivation of AdeS

相反，由于ADE失活而过度表达AdeAB（C）的菌株

have also been reported. These opposing findings emphasize the complexity of this regulatory system. Another intriguing observation is that deletion of

也有报道。这些相反的发现强调了这种监管体系的复杂性。另一个有趣的观察结果是删除

adeS

在里面

A. baumannii

led to increased sensitivity to sulbactam, which is not a substrate of AdeAB(C) while conferring resistance to tigecycline, which is a substrate

导致对舒巴坦的敏感性增加，舒巴坦不是AdeAB（C）的底物，而对替加环素（一种底物）具有抗性

. This “seesaw effect” could be due to an underlying, broader regulon involving AdeR. This is not uncommon for TCSs; indeed, there are indications that AdeRS influences

这种“跷跷板效应”可能是由于涉及AdeR的潜在的，更广泛的调节子。这对于TCS来说并不罕见；事实上，有迹象表明，广告人会影响

A. baumannii

motility, biofilm formation, and virulence, indicating a wider regulome

运动性，生物膜形成和毒力，表明调节范围更广

. Additionally, biophysical and structural data have revealed two amino acid mutations within the dimerization site of AdeR that abolishes dimer formation and subsequent DNA binding

此外，生物物理和结构数据揭示了AdeR二聚化位点内的两个氨基酸突变，这些突变消除了二聚体的形成和随后的DNA结合

. Further molecular dynamic studies of AdeS and AdeR—and mutations of each—are needed to better understand its response to antimicrobial substrates and the consequent regulation of AdeAB(C).

。需要对ADE和AdeR及其突变进行进一步的分子动力学研究，以更好地了解其对抗菌底物的反应以及随后对AdeAB的调节（C）。

AdeAB(C) may also be modulated by other regulatory systems (Fig.

AdeAB（C）也可以由其他调节系统调节（图）。

). As mentioned above, BaeSR is a TCS and global regulator that modulates the expression of AdeAB in the presence of tigecycline in

)。如上所述，BaeSR是一种TCS和全局调节剂，可在替加环素存在下调节AdeAB的表达

A. baumannii

A.鲍曼不动杆菌

; however, DNA binding studies showed that BaeR does not directly bind to the upstream region of

；但是，DNA结合研究表明，BaeR不直接结合到

adeAB(C)

adeAB（C）

, indicating possible regulatory crosstalk with AdeSR

，表明可能与AdeSR发生监管串扰

. Another potential master regulator that may repress

adeAB(C)

adeAB（C）

is the broad stress-responsive protein DksA. DksA binds to RNA polymerase and allosterically modulates its activity, thereby modulating transcription

是广泛的应激反应蛋白DksA。DksA与RNA聚合酶结合并变构调节其活性，从而调节转录

. Additionally, the histone-like nucleoid structuring protein (H-NS), a DNA-binding factor, may also act as a potential repressor of

此外，组蛋白样类核结构蛋白（H-NS）是一种DNA结合因子，也可能作为潜在的阻遏物

adeAB(C)

adeAB（C）

Activity of the TCSs is not only modulated by antibiotics but also by diverse environmental stimuli such as pH, temperature, and osmolarity

TCS的活性不仅受抗生素的调节，还受多种环境刺激（例如pH，温度和渗透压）的调节

. We previously demonstrated the responsiveness of AdeSR to saline stress in

我们之前证明了AdeSR对盐水胁迫的反应

A. baumannii

and many molecules, including human serum albumin

和许多分子，包括人血清白蛋白

and polyamines within blood serum, have been shown to increase AdeAB(C) expression

血清中的多胺和多胺已被证明可以增加AdeAB（C）的表达

. This highlights the responsiveness of the AdeSR system to host-conferring conditions encountered during infection independent of the stress created by the presence of antimicrobial drugs. Understanding this is vital as any factor that affects mutation within the regulatory components may lead to enhanced antibiotic resistance due to efflux pump dysregulation.

这突出了AdeSR系统对感染期间遇到的宿主赋予条件的反应性，而与抗菌药物的存在所产生的压力无关。了解这一点至关重要，因为任何影响调节成分突变的因素都可能由于外排泵失调而导致抗生素耐药性增强。

Appreciating all the triggers that influence the expression of AdeAB(C) could aid in the development of effective efflux inhibitors and help control MDR .

了解影响AdeAB（C）表达的所有触发因素可以帮助开发有效的外排抑制剂并帮助控制MDR。

A. baumannii

Regulation of AdeIJK

AdeIJK法规

AdeN is the known primary regulator of the AdeIJK efflux pump (Fig.

AdeN是已知的AdeIJK外排泵的主要调节器（图）。

). AdeN belongs to the TetR family of regulators which consist of a highly conserved helix-turn-helix motif in the N-terminus and a ligand-binding domain in the C-terminus

)。AdeN属于TetR调节子家族，由N端高度保守的螺旋-转-螺旋基序和C端的配体结合域组成

. TetR regulators typically dimerize and bind to a palindromic sequence located upstream of a gene, activating or repressing its expression. AdeN operates as a repressor so that in the presence of an as-yet-unknown effector, it fails to bind its DNA target and gene transcription proceeds. In this way, AdeN finely tunes the constitutive expression of AdeIJK at a critical threshold.

TetR调节剂通常二聚化并结合位于基因上游的回文序列，激活或抑制其表达。亚丁作为阻遏物起作用，因此在存在尚未知的效应子的情况下，它无法结合其DNA靶标，基因转录也会进行。通过这种方式，亚丁在临界阈值处微调了AdeIJK的组成型表达。

. Constant, low-level expression of AdeIJK plays a pivotal role in the intrinsic resistance of

AdeIJK的持续低水平表达在其内在抗性中起着关键作用

A. baumannii

A.鲍曼不动杆菌

to antibiotics

抗生素

. Indeed, AdeIJK has been shown to efflux clinically important antibiotics such as β-lactams, tetracyclines, and fluoroquinolones

事实上，AdeIJK已被证明可以外排临床上重要的抗生素，如β-内酰胺类、四环素类和氟喹诺酮类

AdeN and AdeIJK are notably conserved and consistently present in the core genome

AdeN和AdeIJK是非常保守的，并且一直存在于核心基因组中

suggesting that they are crucial elements for

Acinetobacter

不动杆菌

survival. For example, recent studies indicate that AdeIJK can contribute to membrane lipid homeostasis to protect against host-generated polyunsaturated fatty acids

生存。例如，最近的研究表明，AdeIJK可以促进膜脂质稳态，以防止宿主产生的多不饱和脂肪酸

. Additional insight into the physiological substrates of AdeIJK may help identify the natural effector ligands that promote efflux pump gene expression and better understand its function beyond antibiotic efflux. Knowing this may tell us how

对AdeIJK生理底物的进一步了解可能有助于鉴定促进外排泵基因表达的天然效应配体，并更好地了解其在抗生素外排之外的功能。了解这一点可能会告诉我们如何

Acinetobacter

不动杆菌

species can bypass the need for adaptive evolution of

物种可以绕过适应性进化的需要

adeIJK

再见

under antibiotic stress and exert intrinsic resistance to antibiotics.

在抗生素压力下，对抗生素产生内在抗性。

The genomic arrangement of

基因组排列

adeN

亚丁

is quite unique for a primary regulator of an RND efflux system in that it is encoded quite distant from the

对于RND外排系统的主要调节器来说是非常独特的，因为它的编码距离

adeIJK

阿德伊克

operon, more typical of a global regulator and unlike the local regulators of the other RND efflux systems which are proximate to the pump-encoding genes

操纵子，更典型的全球调节器，与其他RND外排系统的局部调节器不同，后者与泵编码基因相近

. Interestingly, no local regulator has been identified for the

有趣的是，尚未确定当地监管机构

adeIJK

再见

operon

操纵子

. The reason behind this distinctive arrangement remains an intriguing question. Similar to other TetR family regulators, it is possible that AdeN is a global regulator with a wide regulome

。这种独特安排背后的原因仍然是一个有趣的问题。与其他TetR家族监管机构相似，亚丁可能是一个监管范围广泛的全球监管机构

In contrast to the

与之相反

adeSR

阿德斯尔

regulatory system, the mutational landscape of

监管体系，突变的景观

adeN

亚丁

remains less explored. Studies indicate that amino acid substitutions and deletions in AdeN are primarily distributed within the dimerization domain of the regulator and occasionally within its predicted DNA binding domain

仍然较少探索。研究表明，AdeN中的氨基酸取代和缺失主要分布在调节剂的二聚化结构域内，偶尔也分布在其预测的DNA结合结构域内

. These mutations lead to varying levels of

这些突变导致不同程度的

adeIJK

再见

upregulation

上调

. Insertion sequence (IS) elements are also frequently detected in

。插入序列（IS）元素也经常在

adeIJK

再见

overexpressing mutants. For example, resistance to tigecycline has been associated with IS elements

过表达突变体。例如，对替加环素的耐药性与IS元素有关

ISAba1

ISAba27

, and

，以及

ISAba125

; and

；以及

ISAba11

has been linked with ciprofloxacin resistance

与环丙沙星耐药性有关

. The usual consequence of these insertions is disruption of

。这些插入的通常后果是破坏

adeN

亚丁

or its target sites, leading to increased expression of

或其靶位点，导致表达增加

adeIJK

阿德伊克

. Interestingly, downregulation of

有趣的是，下调

adeN

亚丁

is observed upon

观察时间

ISAba13

insertion within the

插入到

adeN

亚丁

promoter in response to erythromycin and host-derived unsaturated fatty acids

启动子对红霉素和宿主来源的不饱和脂肪酸的反应

. Together, this suggests that various stressors influence the IS type and the genomic location of the insertions; how this happens has not yet been discovered.

总之，这表明各种压力因素会影响IS类型和插入的基因组位置；这种情况是如何发生的还没有被发现。

Overexpression of AdeIJK has also been observed independent of mutations in AdeN

AdeIJK的过度表达也被观察到与AdeN突变无关

suggesting that the a

建议a

deIJK

德IJK

operon may be regulated by other factors—one of which may be the histone-like nucleoid structuring (H-NS) protein

操纵子可能受其他因素调节，其中之一可能是组蛋白样类核结构（H-NS）蛋白

. In

.英寸

A. baumannii

, inactivation of H-NS led to significantly elevated expression of

，H-NS的失活导致

adeIJK

再见

(as well as

（以及

adeAB(C)

adeAB（C）

)

, and

，以及

hns

complementation restored efflux-associated resistance phenotypes. Other studies demonstrated that stress response regulator DksA

互补恢复了外排相关的抗性表型。其他研究表明，应激反应调节剂DksA

, alterations in (p)ppGpp levels

，ppGpp水平的变化

, and oxidative stress-mediated

，以及氧化应激介导的

soxR

expression significantly altered AdeIJK expression

表达显着改变了AdeIJK的表达

hinting that AdeIJK may partake in various cellular stress responses and is conditionally tuned by the involvement of multiple regulators. Indeed, high-level overexpression of AdeIJK is not often seen in clinical isolates of

暗示AdeIJK可能参与各种细胞应激反应，并通过多个监管机构的参与进行有条件的调整。事实上，AdeIJK的高水平过表达在临床分离株中并不常见

A. baumannii

as exceeding normal levels of tripartite, membrane-spanning structures is energetically costly, may impact membrane fluidity, or may even force the cell to expel essential metabolites

由于超过正常水平的三联体，跨膜结构的能量消耗很大，可能会影响膜的流动性，甚至可能迫使细胞排出必需的代谢物

. Why this is different from AdeAB(C)-overexpressing MDR isolates and the reason for the heterogeneity in AdeIJK expression are areas that require further investigation. Moreover, studies on these alternative regulators may clarify the downregulatory mechanisms of AdeIJK.

为什么这与AdeAB（C）过表达的MDR分离株不同，以及AdeIJK表达异质性的原因是需要进一步研究的领域。此外，对这些替代监管机构的研究可能会澄清AdeIJK的下调机制。

Regulation of AdeFGH

AdeFGH的监管

A LysR-type regulator, AdeL, serves as the local transcriptional controller of AdeFGH

LysR型调节因子AdeL是AdeFGH的局部转录调控因子

(Fig.

（图。

). This family of regulators is the most abundant in bacteria and governs crucial pathways including amino acid biosynthesis, oxidative stress response, ion transport, and antibiotic resistance

)。这个调节剂家族是细菌中最丰富的，它控制着关键的途径，包括氨基酸生物合成、氧化应激反应、离子转运和抗生素耐药性

. The regulator—which can act as an activator or repressor in response to an effector—usually functions as a homotetramer, each subunit containing a well-conserved helix-turn-helix DNA-binding domain at the N-terminus connected to an effector-binding domain

调节因子可以作为效应子的激活剂或阻遏物，通常起同四聚体的作用，每个亚基在N端包含一个保守的螺旋-转角-螺旋DNA结合结构域，该结构域与效应子结合结构域相连

AdeFGH is normally maintained at low levels in

AdeFGH通常在

A. baumannii

and is seemingly a minor contributor to the inherent antibiotic resistance of this microbe

并且似乎是这种微生物固有的抗生素耐药性的次要因素

. Even though AdeFGH and AdeL are not found ubiquitously in

。即使AdeFGH和AdeL在

Acinetobacter

不动杆菌

species, most infection-causing strains express them

物种，大多数引起感染的菌株表达它们

. Indeed, clinical

事实上，临床

A. baumannii

isolates resistant to tigecycline and fluoroquinolones have been shown to overexpress AdeFGH

对替加环素和氟喹诺酮类耐药的分离株已被证明过度表达AdeFGH

. Under inducing conditions in the laboratory, AdeFGH has been observed to efflux of a range of antimicrobial substrates such as chloramphenicol, clindamycin, trimethoprim, sulfonamides, and nalidixic acid

在实验室的诱导条件下，已观察到AdeFGH会流出一系列抗菌底物，例如氯霉素，克林霉素，甲氧苄啶，磺酰胺和萘啶酸

AdeL is a repressor of

AdeL是

adeFGH

. Studies have shown that mutations in the C-terminus of AdeL created by selective pressure in vitro increased

研究表明，体外选择性压力产生的AdeL C末端突变增加

adeFGH

expression up to 600-fold

表达高达600倍

. Similarly, other works have suggested that mutations in the predicted ligand and DNA binding domains may activate constitutive

同样，其他研究表明，预测的配体和DNA结合域中的突变可能激活组成型

adeFGH

expression

表达

. The exact functional mechanism of these mutations is unknown as studies have yet to map the binding site of AdeL or determine its putative effectors.

这些突变的确切功能机制尚不清楚，因为研究尚未绘制AdeL的结合位点或确定其推定的效应子。

AdeFGH overexpression is rarely observed during in vitro studies using basal media, even under the pressure of known substrates, leading to the idea that physiological substrates may act as AdeL effectors. For example, subinhibitory concentrations of the known substrate tigecycline have been shown to downregulate AdeFGH.

在使用基础培养基的体外研究中，即使在已知底物的压力下，也很少观察到AdeFGH过表达，这导致了生理底物可能充当AdeL效应子的想法。例如，已知底物替加环素的亚抑制浓度已显示下调AdeFGH。

while pleural fluid and human serum albumin upregulated expression of the pump operon

而胸水和人血清白蛋白上调了泵操纵子的表达

. But note that host physiological substrates could be involved in an as yet unknown regulatory mechanism of AdeFGH. Unlike the previously discussed RND efflux pumps, AdeFGH has been shown to be influenced by only one global regulator, SoxR, which downregulates

但请注意，宿主生理底物可能参与了AdeFGH尚不清楚的调节机制。与之前讨论的RND外排泵不同，AdeFGH仅受一个全球调节器SoxR的影响，SoxR会下调

adeFGH

expression

表达

The multiple roles of RND efflux regulation for clinical antibiotic resistance, persistence, and infection

RND外排调节在临床抗生素耐药性、持久性和感染中的多重作用

A substantial body of evidence suggests that mutations in regulatory genes leading to low-level upregulation of RND pumps may not necessarily correlate with clinically significant levels of resistance

大量证据表明，导致RND泵低水平上调的调控基因突变可能不一定与临床上显着的耐药水平相关

. Nevertheless, these mutant subpopulations can be persistent or tolerant to antibiotics, potentially progressing to clinically relevant resistance through as yet unknown resistance mechanisms. Using immunosuppressed mouse models, Huo et al.

尽管如此，这些突变亚群可能对抗生素具有持久性或耐受性，可能通过尚不清楚的耐药机制发展为临床相关的耐药性。Huo等人使用免疫抑制小鼠模型。

clearly showed how AdeL mutations within

清楚地显示了AdeL突变是如何在

A. baumannii

persisters progressively enhanced resistance, transitioning from non-clinical levels to high-level AMR while improving bacterial fitness

持久性逐渐增强抵抗力，从非临床水平过渡到高水平AMR，同时改善细菌适应性

. A related study in

.相关研究

Pseudomonas aeruginosa

铜绿假单胞菌

showed how mutations in MexZ (the local regulator of the MexXY-oprM RND efflux pump) resulted in low-level upregulation of the pump, yet facilitated bacterial hiding within lung epithelial cells to reduce antibiotic exposure thereby improving tolerance to antibiotics

显示了MexZ（MexXY oprM RND外排泵的局部调节剂）的突变如何导致泵的低水平上调，但促进了细菌隐藏在肺上皮细胞内以减少抗生素暴露，从而提高了对抗生素的耐受性

Regulator mutations affecting efflux gene expression and the subsequent influence on infection-facilitating phenotypes (e.g., biofilm formation) have also been observed in

影响外排基因表达的调节突变以及随后对感染促进表型（例如生物膜形成）的影响也已在

A. baumannii

A.鲍曼不动杆菌

. In one study, bacterial variants with mutations in the DNA binding domain of AdeL were prevalent in biofilm-forming cells following ciprofloxacin exposure while similarly treated planktonic cells had mutations predominantly in AdeN

在一项研究中，环丙沙星暴露后，AdeL DNA结合域突变的细菌变异体在生物膜形成细胞中普遍存在，而类似处理的浮游细胞主要在AdeN中发生突变

. The “selection” of AdeL variants in biofilm-forming cells correlates well with evidence that overexpression of AdeFGH enhances the transport of acylated homoserine lactones, key cell-cell communication molecules that increase biofilm formation

生物膜形成细胞中AdeL变体的“选择”与AdeFGH的过表达增强了酰化高丝氨酸内酯的转运的证据密切相关，酰化高丝氨酸内酯是增加生物膜形成的关键细胞间通讯分子

. Another study observed that a mutation in AdeR resulted in overexpression of

另一项研究观察到，AdeR突变导致

adeAB(C)

adeAB（C）

leading to successful infection in a mouse lung model

导致小鼠肺部模型成功感染

. Further, insertional inactivation of AdeN caused overexpression of

此外，AdeN的插入失活导致

adeIJK

再见

and a concomitant increase of the lethal

并伴随着致命性的增加

A. baumannii

invasion of mammalian cells

哺乳动物细胞的侵袭

100

. The same study showed that an

。同一项研究表明

adeN

亚丁

knockout strain caused elevated mortality in the

基因敲除菌株导致死亡率升高

Galleria mellonella

画廊间

(waxworm) infection model

（蜡虫）感染模型

100

. Together, these examples point to the realistic opportunity to use efflux pump regulators to control

总之，这些例子指出了使用外排泵调节器进行控制的现实机会

A. baumannii

virulence.

毒力。

It is essential to recognize that modulation of efflux pump expression alone may not fully account for additional phenotypes. Most transcription factors are rarely limited to a single target

必须认识到，仅调节外排泵表达可能无法完全解释其他表型。大多数转录因子很少局限于单个靶标

101

. Thus, it is crucial to determine whether the observed effects are attributable to the RND pump itself or to additional targets of the regulator

因此，至关重要的是要确定观察到的影响是归因于RND泵本身还是归因于监管机构的其他目标

101

. The increasing evidence of RND regulators shaping efflux pump expression heterogeneity and thereby aiding bacterial evasion of antimicrobial treatment in dynamic physiological environments highlights the need to re-evaluate their impact to manage AMR and infection progression more effectively.

越来越多的证据表明，RND调节剂可以塑造外排泵表达的异质性，从而有助于细菌在动态生理环境中逃避抗菌治疗，这突出表明需要重新评估其影响，以更有效地管理AMR和感染进展。

Opportunities to mitigate antimicrobial resistance

缓解抗菌素耐药性的机会

via

通过

RND transcriptional regulators

RND转录调节因子

A variety of tactics can be envisioned to manipulate the regulatory systems of RND efflux pumps. Disruption of regulator function through small molecules or oligonucleotides that inhibit protein-protein, protein-DNA, and protein-effector interactions could be viable options (reviewed elsewhere

可以设想多种策略来操纵RND外排泵的调节系统。通过抑制蛋白质-蛋白质、蛋白质-DNA和蛋白质-效应子相互作用的小分子或寡核苷酸破坏调节功能可能是可行的选择

), each avenue ultimately resulting in the down- or up-regulation of an efflux pump. The best strategy to employ would be dependent on the targeted efflux pump: downregulation of the pump operon would be the most effective option for activator-controlled AdeAB(C), whereas upregulation may be the better option for repressor-controlled AdeIJK and AdeFGH..

)，每种途径最终都会导致外排泵的下调或上调。采用的最佳策略取决于靶向外排泵：泵操纵子的下调将是激活剂控制的AdeAB（C）的最有效选择，而上调可能是阻遏物控制的AdeIJK和AdeFGH的更好选择。。

Targeted downregulation of an efflux pump could be achieved using the effector itself (or potentially mimics thereof) to interfere with the normal function of a regulator

可以使用效应器本身（或可能模仿其）来干扰调节剂的正常功能，从而实现外排泵的靶向下调

102

. The same approach can be imagined using the known repressor proteins

使用已知的阻遏蛋白可以想象出相同的方法

103

. Alternatively, inhibitors against the regulatory elements (protein- or DNA-based) could be used to block efflux pump expression. A promising example is the identification of an inhibitor of MarA, an activator of the RND AcrAB-TolC system in Gram-negative

或者，针对调节元件（基于蛋白质或DNA）的抑制剂可用于阻断外排泵的表达。一个有希望的例子是鉴定MarA抑制剂，这是革兰氏阴性菌中RND-AcrAB-TolC系统的激活剂

Enterobacteriaceae

肠杆菌科

104

Purposeful upregulation of an RND efflux pump may seem counterintuitive to combat AMR, but the burden of overexpression on cellular fitness has been shown to impair bacterial growth

有目的地上调RND外排泵似乎违反了对抗AMR的直觉，但过度表达对细胞适应性的负担已被证明会损害细菌的生长

. The physiological stress forces the cells to upregulate compensatory pathways involved in energy production, maintenance of cytoplasmic pH, and metabolite uptake in an aim to maintain homeostasis

生理压力迫使细胞上调能量产生，维持细胞质pH和代谢物摄取的代偿途径，以维持体内平衡

105

106

107

. Therefore, two-pronged AMR-fighting options may be available. A combined approach of efflux pump overexpression via regulator manipulation and prevention of a stress-induced, “life-saving” metabolic pathway shift is one hopeful strategy

因此，AMR可能有双管齐下的战斗选择。通过调节器操作和预防压力诱导的“挽救生命”代谢途径转变的外排泵过表达的组合方法是一种有希望的策略

105

106

107

. Additionally, overexpression of efflux pumps can lead to “collateral sensitivity”, where improved resistance to one antibiotic increases the susceptibility of the bacteria to another, making a multidrug approach possible

此外，外排泵的过度表达可导致“侧支敏感性”，对一种抗生素的耐药性提高会增加细菌对另一种抗生素的敏感性，从而使多药治疗成为可能

In addition to directly controlling efflux pump expression

除了直接控制外排泵的表达

via

通过

their regulators, specifically manipulating the function of the regulators themselves is another plausible approach to control MDR

他们的监管机构，特别是操纵监管机构本身的功能，是控制MDR的另一种合理方法

A. baumannii

A.鲍曼不动杆菌

. Efflux regulatory elements contain well-defined regions that can be strategically exploited through design of small molecule ligands

外排调节元件包含明确定义的区域，可以通过设计小分子配体进行战略性开发

108

. For example, AdeR has a conserved phosphorylation site and a magnesium binding motif that could be harnessed

例如，AdeR有一个保守的磷酸化位点和一个可以利用的镁结合基序

109

. Similarly, LysR and TetR family regulators have potential ligand-binding pockets

同样，LysR和TetR家族调节剂具有潜在的配体结合口袋

. The unique, fairly conserved primary regulatory elements for each RND efflux pump in

。每个RND外排泵的独特，相当保守的主要调节元件

A. baumannii

could enable the development of targeted therapies that minimize collateral damage to beneficial microbiota and reduce the risk of broad-spectrum resistance. Synergistic treatments are also possible, combining inhibitors of regulatory proteins with existing antibiotics to reduce the required antibiotic dose and extend the longevity of currently used antimicrobial agents.

可以开发靶向疗法，最大程度地减少对有益微生物群的附带损害，并降低广谱耐药的风险。协同治疗也是可能的，将调节蛋白抑制剂与现有抗生素相结合，以减少所需的抗生素剂量并延长目前使用的抗菌剂的寿命。

Such targeting of transcriptional control mechanisms may open a new avenue in antimicrobial therapy, offering an alternative to the traditional approach of directly targeting the bacterial cell wall or replication machinery that are historically prone to evolve resistance.

转录控制机制的这种靶向可能为抗菌治疗开辟了一条新途径，为直接靶向历史上容易产生耐药性的细菌细胞壁或复制机制的传统方法提供了替代方法。

110

Challenges in targeting regulatory elements

针对监管要素的挑战

The most significant challenge in targeting regulatory elements of efflux pumps as potential therapeutic interventions is our limited understanding of these intricate regulatory mechanisms. Achieving optimal activation or inhibition of each regulator depends on knowing their binding affinities to their natural substrates.

将外排泵的调节元件作为潜在的治疗干预措施的最重大挑战是我们对这些复杂的调节机制的理解有限。实现每种调节剂的最佳活化或抑制取决于了解它们与天然底物的结合亲和力。

This, though, may be dependent on their confirmation which may change under different physiological conditions in vivo during an infection. Employing a machine-learning modeling approach may elucidate the regulome and physiological dynamics of the regulators and expedite therapeutic advances.

然而，这可能取决于它们的确认，这可能在感染期间在体内不同的生理条件下发生变化。采用机器学习建模方法可以阐明调节剂的调节和生理动力学，并加速治疗进展。

108

111

112

. Another challenge we face is that regulatory networks controlling RND efflux pumps can be redundant or complex

。我们面临的另一个挑战是，控制RND外排泵的监管网络可能是多余的或复杂的

. Interfering with one regulatory pathway may not sufficiently impair the bacteria as alternative pathways may be evoked. Manipulating transcriptional regulators may also lead to the inadvertent dysregulation of other essential bacterial functions and could lead to unintended toxicity to the patient.

.干扰一种调节途径可能不足以损害细菌，因为可能会诱发其他途径。操纵转录调节因子也可能导致其他基本细菌功能的无意失调，并可能导致对患者的意外毒性。

Understanding the full cellular role of each regulator is critical. A third challenge arises when considering combination therapies or exploiting the phenomenon of collateral sensitivity.

了解每个调节器的完整细胞作用至关重要。当考虑联合治疗或利用侧支敏感性现象时，出现了第三个挑战。

. Ensuring that two molecules—a regulatory effector and an antibiotic, or two antibiotics, as examples—reach the infection site in the correct proportions is crucial

.确保两种分子（一种调节效应物和一种抗生素，或两种抗生素）以正确的比例到达感染部位至关重要

113

. This approach may also be highly dependent on the specific bacterial strain causing the infection and so would need to be specifically tailored. Finally, we also need to be aware that bacteria may develop resistance to inhibitors of regulatory proteins, just as they do to antibiotics,

这种方法也可能高度依赖于引起感染的特定细菌菌株，因此需要专门定制。，

via

通过

mutations in the regulatory proteins themselves or through compensatory mechanisms.

调节蛋白本身或通过补偿机制的突变。

Future directions

未来方向

Identifying highly conserved RND efflux pump transcriptional regulators and elucidating in detail their dynamics, structures, and effectors is crucial for developing broad-spectrum inhibitors against them. Exploration of the roles of these regulators independent of efflux pump expression is significantly lacking.

鉴定高度保守的RND外排泵转录调节因子并详细阐明其动力学，结构和效应子对于开发针对它们的广谱抑制剂至关重要。对这些调节因子独立于外排泵表达的作用的探索显着缺乏。

And, as pathogens encounter many stressors during infection (oxidative, nitrosative, osmotic, nutritional, etc.) and elicit many adaptive metabolic strategies, computational and in vivo models are vital to understand the comprehensive roles played by these transcriptional regulators. There is much to learn, but also much to gain..

并且，由于病原体在感染过程中遇到许多压力源（氧化，亚硝化，渗透，营养等），并引发许多适应性代谢策略，因此计算和体内模型对于理解这些转录调节因子所起的综合作用至关重要。有很多东西需要学习，但也有很多东西需要获得。。

Data availability

数据可用性

No datasets were generated or analysed during the current study.

在当前的研究中，没有生成或分析数据集。

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Acknowledgements

致谢

This work was funded by a Discovery Grant (RGPIN-2021-02902) from the Natural Science and Engineering Research Council of Canada to AK. RLW is supported by the University of Manitoba Graduate Fellowship and the Faculty of Science Enhancement of Grant Stipends (SEGS) program.

这项工作由加拿大自然科学与工程研究委员会向AK提供的发现资助（RGPIN-2021-02902）资助。RLW得到了曼尼托巴大学研究生奖学金和科学院补助金增强计划（SEGS）的支持。

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Department of Microbiology, University of Manitoba, Winnipeg, MB, Canada

Ruwani L. Wimalasekara, Dawn White & Ayush Kumar

Ruwani L. Wimalasekara，黎明白色 & Ayush Kumar

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Ruwani L. Wimalasekara

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R.L.W.: conceptualization, writing–original draft preparation, writing–review and editing. D.W.: writing–review and editing. A.K.: conceptualization, funding acquisition, writing review, and editing.

R、 L.W.：概念化，写作-原稿准备，写作-审查和编辑。D、 W.：写作-评论和编辑。A、。

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Wimalasekara, R.L., White, D. & Kumar, A. Targeting

Wimalasekara，R.L.，White，D。和Kumar，A。目标

Acinetobacter baumannii