Inhibitors against serine β-lactamases

Structure-based development of non-β-lactam inhibitors against serine β-lactamases

이화여자대학교  이미지

Class C β-lactamase 

& antibiotics candidate  

β-Lactams (penicillins, cephalosporins, and carbapenems) are the most widely used antibiotics to treat bacterial infections. Clinical application of β-lactams has been accompanied by the emergence of bacterial resistance to these antibiotics, which is a great threat to public health. Expression of β-lactamases is a prevalent resistance mechanism of bacteria to β-lactams. β-Lactamases inactivate β-lactams by hydrolyzing the amide bond in the β-lactam ring, the core structure of β-lactams. They are grouped into four classes, A, B, C and D, on the basis of sequence homology among which class A, B, and D are serine β-lactamases and metallo-β-lactamases belong to class B. Although class C β-lactamases along with class A enzymes are the most commonly encountered of the four classes in clinics, class C β-lactamases are more problematic than class A enzymes. Class C β-lactamases can confer resistance to cephamycins (cefoxitin and cefotetan), penicillins, and cephalosporins and are not significantly inhibited by clinically used β-lactamase inhibitors. In contrast, class A β-lactamases are not able to confer resistance to cephamycins and the enzymes are generally susceptible to inhibition by clinically-used inhibitors. 

The development of inhibitors against β-lactamases is an effective strategy to cope with the β-lactamase-mediated antibiotic resistance since β-lactams maintain their antibiotic activity in the presence of inhibitors that block β-lactamases. In fact, three classical β-lactam inhibitors (clavulanate, sulbactam, and tazobactam) sharing the β-lactam backbone are clinically used in combination with β-lactam antibiotics (e.g. amoxicillin-clavulanate, ticarcillin-clavulanate, ampicillin-sulbactam , piperacillin-tazobactam, and cefoperazone-sulbactam). These clinical inhibitors are especially active on class A enzymes, displaying much less or no effect on other β-lactamaases. Furthermore, β-lactamases resistant to the β-lactam inhibitors are emerging, which highlights the need to develop non-β-lactam inhibitors with broad-spectrum efficacy. 

Our research team has discovered non-β-lactam inhibitors against serine β-lactamases from cellular metabolites. The inhibitors are most effective against class C β-lactamases with extended substrate spectrum. The chemical structures of these novel inhibitors are different from those of existing inhibitors. Remarkably, one of them exhibited an in vivo efficacy without side-effects in mouse models. One concern regarding these inhibitors is their low affinity toward target enzymes, which is the cause of high dose for efficacy in vivo. To overcome the low affinity through designing potent inhibitors, we will reveal the crystal structures of the complexes between β-lactamases and these inhibitors, which will provide an invaluable platform to modify the structure of these novel inhibitors and also to understand their inhibition mechanisms. Our final goal is to develop non-β-lactam inhibitors that are effective towards all serine β-lactamases.

[Related publications]

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Journal of Biotechnology, July 22 accepted (2022)


Yunseok Heo, Soo-Bong Park, Ye-Eun Jeon, Ji-Hye Yun, Bo-Gyeong JeongSun-Shin Cha*, Weontae Lee*

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Acta Crystallogr D structural Biology, Feb 22 accepted (2022)

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Da-Woon BaeYe-Eun Jung, Young Jun An, Jung-Hyun NaSun-Shin Cha*

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Jung-Hyun Na, Tae Hee LeeSoo-Bong Park, Min-Kyu Kim, Bo-Gyeong Jeong, Kyung Min Chung*Sun-Shin Cha*

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Frontiers in Cellular and Infection Microbiology, 8:441 (2018)

Jung-Hyun NaYoung Jun An and Sun-Shin Cha*

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Min-Kyu KimYoung Jun AnJung-Hyun Na, Jae-Hee Seol, Ju Yeon Ryu,Jin-Won Lee, Lin-Woo Kang, Kyung Min Chung, Jung-Hyun Lee, Jeong Hee Moon, Jong Seok Lee, and Sun-Shin Cha*
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Sun-Shin Cha*and Young Jun An

"Crystal structure of EstSRT1, a family VIII carboxylesterase displaying hydrolytic activity toward oxyimino cephalosporins"

Biochemical and Biophysical Research Communications, Sep 16;478(2):818-824 (2016)

Jung-Hyun Na and Sun-Shin Cha*

"Structural basis for the extended substrate spectrum of AmpC BER and structure-guided discovery of the inhibition activity of citrate against the class C β-lactamases AmpC BER and CMY-10"

Acta Crystallogr D Structural Biology, D72, 976-985 (2016)

Sun-Shin Cha*, Young Jun An, Chang-Sook Jeong,Min-Kyu Kim, Jeong Ho Jeon, Chang-Muk Lee, Hyun Sook Lee, Sung Gyun Kang, and Jung-Hyun Lee

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Jae Young Kim, Ha Il JungYoung Jun An, Jung Hun Lee, So Jung Kim, Seok Hoon Jeong, Kye Joon Lee, Pann-Ghill Suh, Heung-Soo Lee, Sang Hee Lee* and Sun-Shin Cha*

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Molecular Microbiology, May;60(4):907-916 (2006)

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[Opinions & Correspondences]

-Sang Hee Lee, Seok Hoon Jeong, Sun-Shin Cha

"Strategies to minimise antibiotic resistance"

The Lancet Infectious Diseases, Nov;5(11):668-670 (2005)

-Sang Hee Lee, Seok Hoon Jeong, Sun-Shin Cha

"Screening for carbapenem-resistant Gram-negative bacteria"

The Lancet Infectious Diseases, Nov;6(11):662-684 (2006)

-Sang Hee Lee, Jung Hun Lee, Myong Jin Heo, Il Kwon Bae, Seok Hoon Jeong, Sun-Shin Cha

"Exact location of the region responsible for the extended substrate spectrum in class C β-lactamases"

Antimicrob Agents Chemother., Oct;51(10): 3778-3779 (2007)

-Jung Hun Lee, Seok Hoon Jeong, Sun-Shin Cha, Sang-Hee Lee

"A lack of drugs for antibiotic resistant Gram-negative bacteria"

Nature Reviews Drug Discovery, Nov;6, 938-939 (2007)

-Jung Hun Lee, Seok Hoon Jeong, Sun-Shin Cha, Sang Hee Lee

"New disturbing trend in antimicrobial resistance of Gram-negative pathogens"

PLoS Pathogens, Mar;5(3):e1000221 (2009)